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Curcumin as a Natural Remedy for Atherosclerosis: A Pharmacological Review

Centre of Biodiversity Conservation & Management, G.B.Pant National Institute of Himalayan Environment, Almora 263643, Uttarakhand, India
School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, Punjab, India
Department of Endocrinology, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230037, China
Department of Pharmacy, Huadu District People’s Hospital, Southern Medical University, Guangzhou 510800, China
Authors to whom correspondence should be addressed.
Molecules 2021, 26(13), 4036;
Received: 29 March 2021 / Revised: 27 June 2021 / Accepted: 28 June 2021 / Published: 1 July 2021
(This article belongs to the Special Issue Natural Products for Cardiovascular Disease)


Curcumin, a natural polyphenolic compound present in Curcuma longa L. rhizomes, shows potent antioxidant, anti-inflammatory, anti-cancer, and anti-atherosclerotic properties. Atherosclerosis is a comprehensive term for a series of degenerative and hyperplasic lesions such as thickening or sclerosis in large- and medium-sized arteries, causing decreased vascular-wall elasticity and lumen diameter. Atherosclerotic cerebro-cardiovascular disease has become a major concern for human health in recent years due to its clinical sequalae of strokes and heart attacks. Curcumin concoction treatment modulates several important signaling pathways related to cellular migration, proliferation, cholesterol homeostasis, inflammation, and gene transcription, among other relevant actions. Here, we provide an overview of curcumin in atherosclerosis prevention and disclose the underlying mechanisms of action of its anti-atherosclerotic effects.

1. Introduction

Atherosclerosis is a common cause of cerebro-cardiovascular disease and is an age-related chronic large-artery condition that develops in adult and aged patients [1]. The pathogenesis of atherosclerosis is multifaceted. Numerous investigations have highlighted hyperlipidemia, diabetes, smoking, hypertension, and other cardiovascular risk factors which mediate oxidative stress causing damage to vascular endothelial cells. They also cause infiltration of low-density lipoproteins (LDL) into the sub-endothelial space, monocyte chemotaxis, aggregation below the endothelium, and platelet activation leading to chronic inflammatory responses in vascular walls [2,3,4,5]. Atherosclerosis is the pathological basis for many cerebro-cardiovascular diseases and acute cerebro-cardiovascular events such as myocardial infarction and ischemic stroke, making it a serious public health concern [6,7]. Anti-arteriosclerotic traditional Chinese medicines (TCM) are widely used in Chinese clinical practice with a good safety profile and lasting efficacy [8,9]. Many traditional medicines used in TCM and other traditional medicine systems such as Ayurveda including turmeric and ginseng have anti-atherosclerotic effects [10,11].
Turmeric prepared from the dried rhizomes of Curcuma longa L. (family, Zingiberaceae) is enriched with multiple bioactive chemical entities with multiple therapeutic applications. The roots and rhizomes of turmeric contain curcumin that has been used as a traditional drug to increase blood circulation and improve stasis [12]. Curcumin has lipid-lowering, antioxidative, anti-inflammatory, and anti-infective effects [13,14,15]. There is growing evidence that curcumin can regulate different signaling molecules to retard the progression and development of atherosclerosis [16]. Similarly, curcumin is also known to regulate inflammatory responses by inhibiting nuclear factor kappa B (NF-κB) expression in atherosclerotic plaques of aortic walls in domestic rabbits and alleviate the severity of atherosclerosis [16].
The mechanistic function of curcumin against atherosclerosis is due at least in part to its anti-inflammatory and anti-oxidative effects and inhibition of vascular smooth muscle cell (VSMC) proliferation and migration. Firstly, inflammation is involved in the entire process of atherosclerosis [17]. According to previous research, curcumin affects inflammatory cells and factors such as inflammation-related enzymes to carry out its anti-inflammatory effects [18,19]. Likewise, curcumin blocks NF-κB signaling to diminish the production of vascular cell-adhesion molecules and inhibit interactions between leukocytes and endothelial cells [20]. Secondly, oxidative stress is a prominent hallmark phenomena that initiates the development of atherosclerosis [21]. Oxidized low-density lipoprotein (oxLDL) is the common link in various aspects of atherosclerosis [22]. Curcumin decreases the sensitivity of LDL towards oxidization, and thus decreases the load of oxidized product to interact with the oxidized low-density lipoprotein receptor 1 (LOX-1) [23]. Curcumin also down regulates inducible nitric oxide synthase activity to inhibit nitro-/oxidative-stress [24]. Thirdly, VSMC proliferation and migration of cells to the intima causes intimal thickening in atherosclerosis. Specifically, neointimal responses associated with artery damage cause proliferation, migration, and collagen synthesis in VSMCs that may increase the susceptibility of blood vessels towards atherosclerosis [25]. Curcumin can increase PPAR-γ activity to inhibit the proliferation of VSMCs [26].
Additionally, epidemiological studies highlight that human cytomegalovirus (HCMV) infection is intimately coupled with the progression and development of atherosclerosis [27]. After entry, HCMV can damage vascular endothelial cells and alter their proliferation [28]. Oral administration of curcumin in ApoE−/− mice inhibits HCMV infection and improves the cellular microenvironment in the host, thereby effectively preventing the development of atherosclerotic lesions [29].

2. Atheroprotective Effects of Curcumin In Vitro

The potential of curcumin in protecting against various medical ailments, including atherosclerosis, has been widely assessed. Atherosclerosis is a chronic inflammatory disease resulting from arterial wall injury, sustained due to dyslipidemia, diabetes, hypertension, and other cardiovascular risk factors that leads to macrophage and VSMC-derived foam cell formation, endothelial cell dysfunction, immune cell activation, platelet activation, and thrombus formation [30,31,32,33]. Several studies have demonstrated curcumin’s potent therapeutic potential in preventing foam cell formation, modulating macrophage polarization, tuning cholesterol efflux, and regulating pro-inflammatory responses [16,34,35,36,37,38].
The anti-atherosclerotic properties of curcumin are expressed through suppressing macrophage polarization (M1 to M2) [39] or by inducing M2 polarization via IL-4 and/or IL-13 secretion in macrophages [40]. Similarly, convincing evidence suggests that curcumin, when acting against macrophages treated with oxLDL, upregulates the expression of thrombospondin-4 (THBS-4) [36] and modulates chemoattractant protein-1 (MCP-1) expression, which represents the anti-inflammatory response [41]. The molecular targets of anti-atherosclerotic effects of curcumin involve upregulation of miR-126, which further inhibits signal transduction and PI3K/AKT and JAK2/STAT5 activation [42]. Other targets of curcumin include NF-κB inhibition in the M1 macrophages, as well as promoting M2 phenotype via PPAR-γ activation. Further, curcumin inhibits toll-like receptor-4 (TLR4), MAPK, and NF-κB signaling in macrophages and VSMCs [43] (Table 1).
TLR4, an important signaling receptor, plays an important role in the pathogenesis of plaque formation and the development of atherosclerosis [73]. Furthermore, TLR4 activates a variety of signal transduction molecules as well as transcription factors. An important response of TLR4 activation is NF-κB and MAPK activation, which triggers nuclear transduction that simultaneously propels the gene expression profile of an inflammatory reaction. The amplified expression profile increases ROS production and the expression of inflammatory molecules, which causes the initiation of atherogenesis, leading ultimately to the clinically critical destabilization of atherosclerotic plaques [16]. Reports on curcumin supplementation fostering negative regulation not only on towards the TLR receptor but also on nuclear transduction molecules and inflammatory cytokines (TNF-α, IL-1β, VCAM-1, ICAM 1, etc.) are presented [74] (Figure 1).
Curcumin has also been shown to inhibit ligand-induced and ligand-independent dimerization at the receptor level. LPS induces activation of both MyD88 and TRIF-dependent signaling via the TLR4 receptor. Upon curcumin supplementation, TLR4 homodimerization was blocked [46], providing a novel mechanism for its anti-inflammatory effects. In a similar fashion, curcumin inhibits the NOD-like receptor (NLR) family, the pyrin domain containing 3 (NLRP3) inflammasome via suppressing TLR4/MyD88/NF-κB, the phosphorylation level of IkB-α, and purinergic 2X7 receptor (P2X7R) pathways in phorbol 12-myristate 13-acetate (PMA)-induced macrophages [55]. NLRP3 inflammasome is composed of a multiprotein complex having caspase and caspase 1 protein complex for apoptosis [75]. On NLRP3 complex stimulation, caspase-1 is activated, which cleaves the pro-forms of interleukin (IL)-1β and IL-18 into their mature forms. Once in fully mature form, IL-1β (a primary pro-inflammatory cytokine) mediates the development of atherosclerosis. Curcumin also inhibits VSMC migration by negatively regulating NLRP3 expression via an NF-κB-mediated response and decreasing IL-1 concentration [55].
In VSMCs, curcumin supplementation markedly reduces inflammatory responses induced by LPS acting at TLR4. LPS induced stimulation of TRL4 increases the phosphorylation of IκBα, NF-κB (p65), and MAPKs [59]. Concurrently, this increases the inflammatory cytokine expression profile of TLR4, MCP-1, iNOS, TNF-α, and NO production. In addition, Meng et al. (2013) [59] established that curcumin supplementation inhibits TLR4 activation and ERK1/2 and p38 MAPK phosphorylation, thereby preventing NF-κB nuclear translocation that mediates ROS production. Thus, inhibition of the expression profile may reduce atherosclerotic plaque formation and reduce inflammatory cell infiltration into the plaques. More recently, Zhang et al. [62] showed that curcumin inhibits aldosterone-induced production of CRP in VSMCs by reducing ROS production via limiting aberrant activation of the ERK1/2 signal pathway.
LDL is another important pathological entity that contributes to the development of atherosclerotic lesions. ROS modifies LDL, thereby producing Ox-LDL. An increase in Ox-LDL concentration in plasma has long been recognized as a key factor in atherosclerosis. Ox-LDL, rather than binding to LDL receptor, binds to scavenger receptors (SRs). The major SR is CD36 that recognizes ox-LDL [76]. After binding to CD36 on cell membrane, ox-LDL can also trigger CD36 expression via PPAR-γ pathway [77]. Specifically, PPAR-γ, once activated, dimerizes with the retinoid X receptor (RXR) and triggers PPAR-response element (PPRE)-containing genes, which ultimately increases CD36 expression, resulting in increased ox-LDL influx [78].
Cholesterol accumulation in macrophages results in foam cell formation and fatty streak development via upregulating the expression/activity of several receptors, such as SR-AI/II, SRBI, CD36, and LOX-1. In contrast, various efflux transporters play an active role via ATP-binding cassette (ABC) transporters ABCA1, ABCG1, and SR-BI to facilitate reverse cholesterol transport from macrophages [79]. Fatty acid-binding protein (FABP)-4 or adipocyte protein 2 (aP2) coordinates cholesterol trafficking (efflux) but is also known to activate an inflammatory response. Lack of aP2 protein complex changes the cholesterol composition in macrophages, which concurrently amplifies CD36 expression and enhances oxLDL influx [80]. This cascade creates a disease state, whereby macrophages induce the release of IL-1β, TNFα, ROS, and matrix metalloproteases coupled with the development of inflammation, cell migration, and plaque formation (Figure 1). Hence, genetic or pharmacological inhibition of aP2 and CD36 expression might offer potential remedies to atherosclerosis.
Several further lines of experimental evidence highlight the potent anti-atherogenic effects of curcumin (documented in Table 1). For example, Zhou et al. (2014) [36] demonstrated that curcumin treatment reduces the expression profile of oxLDL-induced thrombospondins-4 (THBS-4). THBS-4 was reported to influence important cellular responses such as cell migration, proliferation, and adhesion, leading to atherogenesis progression [81]. Curcumin further inhibits p38 MAPK activation and reduces PPAR-γ and CD36 expression in oxLDL-treated macrophages, leading to decreased foam cell formation [77]. In human umbilical vein endothelial cells (HUVECs), curcumin inhibits ROS production, NF-κB-dependent LOX-1 expression, and VCAM-1 and ICAM-1 expression. In addition, curcumin promotes NO production to confer vasodilatory effects [6,7]. Recent studies also suggest that curcumin could reduce oxidative stress, ER stress, and inflammatory response induced by acrolein (a toxin from tobacco smoke) and cytomegalovirus (CMV) infection in human endothelial cells [29,66]. The anti-inflammatory effects of curcumin is exerted through inhibiting COX-2 expression and prostaglandin production via reducing the phosphorylation of PKC, p38 MAPK, and cAMP response element-binding protein as well as inhibiting the HMGB1-TLRS-NF-κB signaling pathway [29,66]. The broad anti-inflammatory effects of curcumin underlie its effects on improving flow-mediated dilation in human subjects [82].

3. Atheroprotective Effects of Curcumin In Vivo

Numerous lines of experimental evidence (Table 2) support the actions of curcumin in reducing the cardiovascular risk associated with atherosclerosis.

4. Clinical Studies of Curcumin

Few clinical trials involving double-blind placebo-controlled studies and randomized controlled trials have been undertaken. A 12-week randomized placebo-controlled trial of 118 participants showed that curcumin treatment reduced the risk of developing acute cardiovascular events in people with type 2 diabetes and dyslipidemia [95]. Another randomized controlled research with 87 patients found that taking 1 g of curcumin for eight weeks lowered TC, TG, and HDL-c levels following nonalcoholic fatty liver infections [96]. On the other hand, curcumin lowered LDL-c and Apo B and increased Apo A1 and HDL-c levels in healthy people, indicating anti-atherosclerosis efficacy [97]. In coronary bypass graft, curcumin (4 g/day) reduced acute myocardial infarction and significantly decreased malondialdehyde levels [98]. Further, in patients with chronic obstructive pulmonary disease, curcumin (Theracurmin® 90 mg/day for 24 weeks) reduced the level of the α1-antitrypsin–low-density lipoprotein (AT-LDL) complex, which promotes arteriosclerosis [99]. In another randomized trial, curcumin usage at 80 mg per day ameliorated dyslipidemia in patients with reduced serum TG, salivary amylase, and β-amyloid levels and increased plasma nitric oxide level after four weeks of study [100]. Likewise, in a double-blind placebo-controlled study, curcumin (200 mg) supplementation improved endothelial function measured by flow-mediated dilation (FMD), thus decreasing the risk of cardiovascular diseases [101]. In another pilot study, curcumin (500 mg/day for 12 weeks) de-stiffened arteries in young, obese men with aortic stiffness [102]. Studies with curcumin have potential limitations due to factors such as limited sample sizes; therefore, large-scale clinical trials are required to characterize the actual potential and identify the direct molecular targets of curcumin in treating atherosclerosis.

5. Conclusions and Perspectives

Substantial experimental evidence suggests that curcumin prevents endothelial dysfunction, smooth muscle cell proliferation and migration, and foam cell formation and modulates macrophage polarization. Curcumin also counteracts inflammatory response, supporting its potential application in atherosclerosis treatment. The anti-atherosclerotic properties of curcumin occur through suppressing inflammatory response by skewing macrophage polarization from M1 to M2 or by inducing M2 polarization through regulating TLR4/MAPK/NF-κB pathways in macrophages and secretion of interleukins (IL-4 and/or IL-13). Similarly, curcumin concurrently regulates the expression and activity of the lipid transporter expression (CD36, CD38, ABCA1, aP2, etc.) responsible for cholesterol uptake and efflux, thus maintaining cell homeostasis. In addition, curcumin lowers the circulating level of ox-LDL and blocks oxLDL elicited pro-atherogenic events by decreasing the expression of MCP-1 and THBS-4 via the p38 MAPK and NF-κB pathways [52]. Likewise, curcumin suppresses TLR4 expression and macrophage infiltration in aortic tissues and protects against atherosclerotic plaque formation [16]. A recent study has suggested that curcumin blocks LPA-induced MCP-1 expression via TGFBR1/ROCK signaling pathway [103].Additional studies are required to improve or add meaningful insights into our understanding of the mechanism(s) of action of curcumin against atherosclerosis, especially in the clinical setting. In addition, the development of novel drug delivery systems, such as the creation of curcumin nanomicelles [104,105], is critical for improving the oral bioavailability of curcumin which may contribute to its clinical efficacy [106].

Author Contributions

Conceptualization, S.X., D.T. and J.F.; data curation, L.S., S.S. and D.T.; writing—original draft preparation, L.S., J.F. and D.T.; writing—review and editing, S.X., D.T. and J.F.; supervision, S.X.; funding acquisition, S.X. All authors have read and agreed to the published version of the manuscript.


This study was partially supported by grants from Natural Science Foundation of China (No. 82070464).


D.T. and S.S. express their gratitude towards Management, Senior Dean and CoD of Lovely Professional University, Punjab, India for providing necessary facilities and time to conduct the study. The authors are grateful to Peter J. Little (University of Sunshine Coast, Australia) for proofreading and editing of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Hannawi, S.; Hannawi, H.; Al Salmi, I. Cardiovascular disease and subclinical atherosclerosis in rheumatoid arthritis. Hypertens. Res. 2020, 43, 982–984. [Google Scholar] [CrossRef] [PubMed]
  2. Bi, C.; Fu, Y.; Li, B. Brain-derived neurotrophic factor alleviates diabetes mellitus-accelerated atherosclerosis by promoting M2 polarization of macrophages through repressing the STAT3 pathway. Cell. Signal. 2020, 70, 109569. [Google Scholar] [CrossRef]
  3. Ito, K.; Maeda, T.; Tada, K.; Takahashi, K.; Yasuno, T.; Masutani, K.; Mukoubara, S.; Arima, H.; Nakashima, H. The role of cigarette smoking on new-onset of chronic kidney disease in a Japanese population without prior chronic kidney disease: Iki epidemiological study of atherosclerosis and chronic kidney disease (ISSA-CKD). Clin. Exp. Nephrol. 2020, 24, 919–926. [Google Scholar] [CrossRef] [PubMed]
  4. Miao, J.; Zang, X.; Cui, X.; Zhang, J. Autophagy, Hyperlipidemia, and Atherosclerosis. Adv. Exp. Med. Biol. 2020, 1207, 237–264. [Google Scholar] [CrossRef] [PubMed]
  5. Ye, J.; Wang, Y.; Wang, Z.; Liu, L.; Yang, Z.; Wang, M.; Xu, Y.; Ye, D.; Zhang, J.; Zhou, Q.; et al. The Expression of IL-12 Family Members in Patients with Hypertension and Its Association with the Occurrence of Carotid Atherosclerosis. Mediat. Inflamm. 2020, 2020, 2369279. [Google Scholar] [CrossRef][Green Version]
  6. Ntaios, G.; Pearce, L.A.; Meseguer, E.; Endres, M.; Amarenco, P.; Ozturk, S.; Lang, W.; Bornstein, N.M.; Molina, C.A.; Pagola, J.; et al. Aortic Arch Atherosclerosis in Patients with Embolic Stroke of Undetermined Source: An Exploratory Analysis of the NAVIGATE ESUS Trial. Stroke 2019, 50, 3184–3190. [Google Scholar] [CrossRef]
  7. Pomozova, T.P.; Lykov, Y.V.; Komarova, I.S.; Dyatlov, N.V.; Zhelnov, V.V. Clinical and laboratory features of primary acute myocardial infarction in patients with obstructive and non-obstructive coronary atherosclerosis. Kardiologiia 2019, 59, 41–51. [Google Scholar] [CrossRef] [PubMed]
  8. Kim, S.H.; Park, K.S. Effects of Panax ginseng extract on lipid metabolism in humans. Pharmacol. Res. 2003, 48, 511–513. [Google Scholar] [CrossRef]
  9. Liu, J.; Zhang, J.; Shi, Y.; Grimsgaard, S.; Alraek, T.; Fønnebø, V. Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: A meta-analysis of randomized controlled trials. Chin. Med. 2006, 1, 1–13. [Google Scholar] [CrossRef][Green Version]
  10. Ramírez-Tortosa, M.C.; Mesa, M.D.; Aguilera, M.C.; Quiles, J.L.; Baró, L.; Ramirez-Tortosa, C.L.; Martinez-Victoria, E.; Gil, A. Oral administration of a turmeric extract inhibits LDL oxidation and has hypocholesterolemic effects in rabbits with experimental atherosclerosis. Atherosclerosis 1999, 147, 371–378. [Google Scholar] [CrossRef]
  11. Chan, G.H.-H.; Law, B.Y.-K.; Chu, J.M.-T.; Yue, K.K.-M.; Jiang, Z.-H.; Lau, C.-W.; Huang, Y.; Chan, S.-W.; Ying-Kit, Y.P.; Wong, R.N.-S. Ginseng extracts restore high-glucose induced vascular dysfunctions by altering triglyceride metabolism and downregulation of atherosclerosis-related genes. Evid. Based. Complement. Altern. Med. 2013, 2013, 797310. [Google Scholar] [CrossRef] [PubMed][Green Version]
  12. Kim, J.H.; Yang, H.J.; Kim, Y.J.; Park, S.; Lee, O.H.; Kim, K.S.; Kim, M.J. Korean turmeric is effective for dyslipidemia in human intervention study. J. Ethn. Foods 2016, 3, 213–221. [Google Scholar] [CrossRef][Green Version]
  13. González-Ortega, L.A.; Acosta-Osorio, A.A.; Grube-Pagola, P.; Palmeros-Exsome, C.; Cano-Sarmiento, C.; García-Varela, R.; García, H.S. Anti-inflammatory Activity of Curcumin in Gel Carriers on Mice with Atrial Edema. J. Oleo Sci. 2020, 69, 123–131. [Google Scholar] [CrossRef] [PubMed][Green Version]
  14. Qin, S.; Huang, L.; Gong, J.; Shen, S.; Huang, J.; Ren, H.; Hu, H. Efficacy and safety of turmeric and curcumin in lowering blood lipid levels in patients with cardiovascular risk factors: A meta-analysis of randomized controlled trials. Nutr. J. 2017, 16, 68. [Google Scholar] [CrossRef] [PubMed]
  15. Song, H.-C.; Chen, Y.; Chen, Y.; Park, J.; Zheng, M.; Surh, Y.-J.; Kim, U.-H.; Park, J.W.; Yu, R.; Chung, H.T.; et al. GSK-3β inhibition by curcumin mitigates amyloidogenesis via TFEB activation and anti-oxidative activity in human neuroblastoma cells. Free Radic. Res. 2020, 1–13. [Google Scholar] [CrossRef]
  16. Zhang, S.; Zou, J.; Li, P.; Zheng, X.; Feng, D. Curcumin Protects against Atherosclerosis in Apolipoprotein E-Knockout Mice by Inhibiting Toll-like Receptor 4 Expression. J. Agric. Food Chem. 2018, 66, 449–456. [Google Scholar] [CrossRef] [PubMed]
  17. Marchio, P.; Guerra-Ojeda, S.; Vila, J.M.; Aldasoro, M.; Victor, V.M.; Mauricio, M.D. Targeting Early Atherosclerosis: A Focus on Oxidative Stress and Inflammation. Oxidative Med. Cell. Longev. 2019, 1, 32. [Google Scholar] [CrossRef]
  18. Chen, Y.-Q.; Chai, Y.-S.; Xie, K.; Yu, F.; Wang, C.-J.; Lin, S.-H.; Yang, Y.-Z.; Xu, F. Curcumin Promotes the Expression of IL-35 by Regulating Regulatory T Cell Differentiation and Restrains Uncontrolled Inflammation and Lung Injury in Mice. Inflammation 2020, 43, 1913–1924. [Google Scholar] [CrossRef]
  19. Zhu, H.; Wang, X.; Wang, X.; Liu, B.; Yuan, Y.; Zuo, X. Curcumin attenuates inflammation and cell apoptosis through regulating NF-κB and JAK2/STAT3 signaling pathway against acute kidney injury. Cell Cycle 2020, 19, 1941–1951. [Google Scholar] [CrossRef]
  20. Olszanecki, R.; Jawień, J.; Gajda, M.; Mateuszuk, L.; Gebska, A.; Korabiowska, M.; Chłopicki, S.; Korbut, R. Effect of Curcumin on atherosclerosis in apoE/LDLR-double knockout mice. J. Physiol. Pharmacol. 2005, 56, 627–635. [Google Scholar]
  21. Xie, M.; Tang, Q.; Nie, J.; Zhang, C.; Zhou, X.; Yu, S.; Sun, J.; Cheng, X.; Dong, N.; Hu, Y.; et al. BMAL1-Downregulation Aggravates Porphyromonas Gingivalis-Induced Atherosclerosis by Encouraging Oxidative Stress. Circ. Res. 2020, 126, e15–e29. [Google Scholar] [CrossRef] [PubMed]
  22. Libby, P.; Ridker, P.M.; Hansson, G.K. Progress and challenges in translating the biology of atherosclerosis. Nature 2011, 473, 317–327. [Google Scholar] [CrossRef]
  23. Kattoor, A.J.; Goel, A.; Mehta, J.L. LOX-1: Regulation, Signaling and Its Role in Atherosclerosis. Antioxidants 2019, 8, 218. [Google Scholar] [CrossRef][Green Version]
  24. Boonla, O.; Kukongviriyapan, U.; Pakdeechote, P.; Kukongviriyapan, V.; Pannangpetch, P.; Prachaney, P.; Greenwald, S.E. Curcumin improves endothelial dysfunction and vascular remodeling in 2K-1C hypertensive rats by raising nitric oxide availability and reducing oxidative stress. Nitric Oxide Biol. Chem. 2014, 42, 44–53. [Google Scholar] [CrossRef][Green Version]
  25. Kapakos, G.; Youreva, V.; Srivastava, A. Cardiovascular protection by curcumin: Molecular aspects. Indian J. Biochem. Biophys. 2012, 49, 306–315. [Google Scholar] [PubMed]
  26. Han, Y.; Sun, H.-J.; Tong, Y.; Chen, Y.-Z.; Ye, C.; Qiu, Y.; Zhang, F.; Chen, A.-D.; Qi, X.-H.; Chen, Q.; et al. Curcumin attenuates migration of vascular smooth muscle cells via inhibiting NFκB-mediated NLRP3 expression in spontaneously hypertensive rats. J. Nutr. Biochem. 2019, 72, 108212. [Google Scholar] [CrossRef]
  27. Horváth, R.; Cerný, J.; Benedík, J.J.; Hökl, J.; Jelínková, I.; Benedík, J. The possible role of human cytomegalovirus (HCMV) in the origin of atherosclerosis. J. Clin. Virol. Off. Publ. Pan Am. Soc. Clin. Virol. 2000, 16, 17–24. [Google Scholar] [CrossRef]
  28. Shen, K.; Xu, L.; Chen, D.; Tang, W.; Huang, Y. Human cytomegalovirus-encoded miR-UL112 contributes to HCMV-mediated vascular diseases by inducing vascular endothelial cell dysfunction. Virus Genes 2018, 54, 172–181. [Google Scholar] [CrossRef] [PubMed]
  29. Lv, Y.-L.; Jia, Y.; Wan, Z.; An, Z.-L.; Yang, S.; Han, F.-F.; Gong, L.-L.; Xuan, L.-L.; Ren, L.-L.; Zhang, W.; et al. Curcumin inhibits the formation of atherosclerosis in ApoE(-/-) mice by suppressing cytomegalovirus activity in endothelial cells. Life Sci. 2020, 257, 117658. [Google Scholar] [CrossRef]
  30. Förstermann, U.; Xia, N.; Li, H. Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis. Circ. Res. 2017, 120, 713. [Google Scholar] [CrossRef]
  31. Di Pietro, N.; Formoso, G.; Pandolfi, A. Physiology and pathophysiology of oxLDL uptake by vascular wall cells in atherosclerosis. Vasc. Pharmacol. 2016, 84, 1–7. [Google Scholar] [CrossRef] [PubMed]
  32. Ahmed, S.; Khan, H.; Mirzaei, H. Mechanics insights of Curcumin in myocardial ischemia: Where are we standing? Eur. J. Med. Chem. 2019, 183, 111658. [Google Scholar] [CrossRef] [PubMed]
  33. Li, C.; Miao, X.; Li, F.; Adhikari, B.K.; Liu, Y.; Sun, J.; Zhang, R.; Cai, L.; Liu, Q.; Wang, Y. Curcuminoids: Implication for inflammation and oxidative stress in cardiovascular diseases. The clinical studies of Curcumin should be summarized and added in the last chapter. Phytother. Res. 2019, 33, 1–16. [Google Scholar] [CrossRef][Green Version]
  34. Li, B.; Hu, Y.; Zhao, Y.; Cheng, M.; Qin, H.; Cheng, T.; Wang, Q.; Peng, X.; Zhang, X. Curcumin Attenuates Titanium Particle-Induced Inflammation by Regulating Macrophage Polarization In Vitro and In Vivo. Front. Immunol. 2017, 8, 55. [Google Scholar] [CrossRef] [PubMed][Green Version]
  35. Momtazi-Borojeni, A.A.; Banach, M.; Majeed, M.; Sahebkar, A. P5330 Evaluating lipid-lowering and anti-atherogenic effect of injectable Curcumin in a rabbit model of atherosclerosis. Eur. Heart J. 2019, 40, ehz746-0299. [Google Scholar] [CrossRef]
  36. Zhou, Z.; Chen, Y.; Wang, F.; Tian, N.; Fan, C. Effect of Curcumin on down-expression of thrombospondin-4 induced by oxidized low-density lipoprotein in mouse macrophages. Biomed. Mater. Eng. 2014, 24, 181–189. [Google Scholar] [CrossRef]
  37. Chen, F.-Y.; Zhou, J.; Guo, N.; Ma, W.-G.; Huang, X.; Wang, H.; Yuan, Z.-Y. Curcumin retunes cholesterol transport homeostasis and inflammation response in M1 macrophage to prevent atherosclerosis. Biochem. Biophys. Res. Commun. 2015, 467, 872–878. [Google Scholar] [CrossRef] [PubMed]
  38. Lin, X.; Liu, M.-H.; Hu, H.-J.; Feng, H.; Fan, X.-J.; Zou, W.; Pan, Y.; Hu, X.; Wang, Z. Curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through AMPK-SIRT1-LXRα signaling in THP-1 macrophage-derived foam cells. DNA Cell Biol. 2015, 34, 561–572. [Google Scholar] [CrossRef] [PubMed]
  39. Karuppagounder, V.; Arumugam, S.; Thandavarayan, R.A.; Sreedhar, R.; Giridharan, V.V.; Afrin, R.; Harima, M.; Miyashita, S.; Hara, M.; Suzuki, K.; et al. Curcumin alleviates renal dysfunction and suppresses inflammation by shifting from M1 to M2 macrophage polarization in daunorubicin induced nephrotoxicity in rats. Cytokine 2016, 84, 1–9. [Google Scholar] [CrossRef]
  40. Gao, S.; Zhou, J.; Liu, N.; Wang, L.; Gao, Q.; Wu, Y.; Zhao, Q.; Liu, P.; Wang, S.; Liu, Y.; et al. Curcumin induces M2 macrophage polarization by secretion IL-4 and/or IL-13. J. Mol. Cell. Cardiol. 2015, 85, 131–139. [Google Scholar] [CrossRef]
  41. Karimian, M.S.; Pirro, M.; Majeed, M.; Sahebkar, A. Curcumin as a natural regulator of monocyte chemoattractant protein-1. Cytokine Growth Factor Rev. 2017, 63, 55–63. [Google Scholar] [CrossRef] [PubMed]
  42. Li, Y.; Tian, L.; Sun, D.; Yin, D. Curcumin ameliorates atherosclerosis through upregulation of miR-126. J. Cell. Physiol. 2019, 234, 21049–21059. [Google Scholar] [CrossRef] [PubMed]
  43. Zhou, Y.; Zhang, T.; Wang, X.; Wei, X.; Chen, Y.; Guo, L.; Zhang, J.; Wang, C. Curcumin Modulates Macrophage Polarization Through the Inhibition of the Toll-Like Receptor 4 Expression and its Signaling Pathways. Cell. Physiol. Biochem. 2015, 36, 631–641. [Google Scholar] [CrossRef] [PubMed]
  44. Jain, S.K.; Rains, J.; Croad, J.; Larson, B.; Jones, K. Curcumin supplementation lowers TNF-alpha, IL-6, IL-8, and MCP-1 secretion in high glucose-treated cultured monocytes and blood levels of TNF-alpha, IL-6, MCP-1, glucose, and glycosylated hemoglobin in diabetic rats. Antioxid. Redox Signal. 2009, 11, 241–249. [Google Scholar] [CrossRef] [PubMed][Green Version]
  45. Hasan, S.T.; Zingg, J.-M.; Kwan, P.; Noble, T.; Smith, D.; Meydani, M. Curcumin modulation of high fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice. Atherosclerosis 2014, 232, 40–51. [Google Scholar] [CrossRef]
  46. Youn, H.S.; Saitoh, S.I.; Miyake, K.; Hwang, D.H. Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem. Pharmacol. 2006, 72, 62–69. [Google Scholar] [CrossRef]
  47. Chen, F.; Guo, N.; Cao, G.; Zhou, J.; Yuan, Z. Molecular analysis of curcumin-induced polarization of murine RAW264.7 macrophages. J. Cardiovasc. Pharmacol. 2014, 63, 544–552. [Google Scholar] [CrossRef] [PubMed]
  48. Wang, J.; Kang, Y.-X.; Pan, W.; Lei, W.; Feng, B.; Wang, X.-J. Enhancement of Anti-Inflammatory Activity of Curcumin Using Phosphatidylserine-Containing Nanoparticles in Cultured Macrophages. Int. J. Mol. Sci. 2016, 17, 969. [Google Scholar] [CrossRef][Green Version]
  49. Ouyang, S.; Yao, Y.-H.; Zhang, Z.-M.; Liu, J.-S.; Xiang, H. Curcumin inhibits hypoxia inducible factor-1α-induced inflammation and apoptosis in macrophages through an ERK dependent pathway. Eur. Rev. Med. Pharmacol. Sci. 2019, 23, 1816–1825. [Google Scholar] [CrossRef]
  50. Keshavarz, Z.; Kheirollah, A.; Ghaffari, M.-A.; Babaahmadi-Rezaei, H. Curcumin Inhibited Endothelin-1 mRNA Expression Induced by TGF-β in Bovine Aortic Endothelial Cell. Jundishapur J. Nat. Pharm. Prod. 2019, 14. [Google Scholar] [CrossRef]
  51. Ameruoso, A.; Palomba, R.; Palange, A.L.; Cervadoro, A.; Lee, A.; Di Mascolo, D.; Decuzzi, P. Ameliorating Amyloid-β Fibrils Triggered Inflammation via Curcumin-Loaded Polymeric Nanoconstructs. Front. Immunol. 2017, 8, 1411. [Google Scholar] [CrossRef][Green Version]
  52. Cao, J.; Ye, B.; Lin, L.; Tian, L.; Yang, H.; Wang, C.; Huang, W.; Huang, Z. Curcumin Alleviates oxLDL Induced MMP-9 and EMMPRIN Expression through the Inhibition of NF-κB and MAPK Pathways in Macrophages. Front. Pharmacol. 2017, 8, 62. [Google Scholar] [CrossRef][Green Version]
  53. Cao, J.; Han, Z.; Tian, L.; Chen, K.; Fan, Y.; Ye, B.; Huang, W.; Wang, C.; Huang, Z. Curcumin inhibits EMMPRIN and MMP-9 expression through AMPK-MAPK and PKC signaling in PMA induced macrophages. J. Transl. Med. 2014, 12, 266. [Google Scholar] [CrossRef] [PubMed][Green Version]
  54. Huang, S.-L.; Chen, P.-Y.; Wu, M.-J.; Tai, M.-H.; Ho, C.-T.; Yen, J.-H. Curcuminoids Modulate the PKCδ/NADPH Oxidase/Reactive Oxygen Species Signaling Pathway and Suppress Matrix Invasion during Monocyte-Macrophage Differentiation. J. Agric. Food Chem. 2015, 63, 8838–8848. [Google Scholar] [CrossRef]
  55. Kong, F.; Ye, B.; Cao, J.; Cai, X.; Lin, L.; Huang, S.; Huang, W.; Huang, Z. Curcumin Represses NLRP3 Inflammasome Activation via TLR4/MyD88/NF-κB and P2X7R Signaling in PMA-Induced Macrophages. Front. Pharmacol. 2016, 7, 369. [Google Scholar] [CrossRef] [PubMed][Green Version]
  56. Zheng, L.; Sun, X.; Zhu, X.; Lv, F.; Zhong, Z.; Zhang, F.; Guo, W.; Cao, W.; Yang, L.; Tian, Y. Apoptosis of THP-1 derived macrophages induced by sonodynamic therapy using a new sonosensitizer hydroxyl acetylated curcumin. PLoS ONE 2014, 9, e93133. [Google Scholar] [CrossRef] [PubMed]
  57. Zhong, Y.; Liu, T.; Guo, Z. Curcumin inhibits ox-LDL-induced MCP-1 expression by suppressing the p38MAPK and NF-κB pathways in rat vascular smooth muscle cells. Inflamm. Res. Off. J. Eur. Histamine Res. Soc. 2012, 61, 61–67. [Google Scholar] [CrossRef]
  58. Hosseinzadeh, L.; Behravan, J.; Mosaffa, F.; Bahrami, G.; Bahrami, A.; Karimi, G. Curcumin potentiates doxorubicin-induced apoptosis in H9c2 cardiac muscle cells through generation of reactive oxygen species. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2011, 49, 1102–1109. [Google Scholar] [CrossRef]
  59. Meng, Z.; Yan, C.; Deng, Q.; Gao, D.; Niu, X. Curcumin inhibits LPS-induced inflammation in rat vascular smooth muscle cells in vitro via ROS-relative TLR4-MAPK/NF-κB pathways. Acta Pharmacol. Sin. 2013, 34, 901–911. [Google Scholar] [CrossRef][Green Version]
  60. Liu, T.; Li, C.; Sun, H.; Luo, T.; Tan, Y.; Tian, D.; Guo, Z. Curcumin inhibits monocyte chemoattractant protein-1 expression and enhances cholesterol efflux by suppressing the c-Jun N-terminal kinase pathway in macrophage. Inflamm. Res. Off. J. Eur. Histamine Res. Soc. 2014, 63, 841–850. [Google Scholar] [CrossRef]
  61. Ahn, J.; Lee, H.; Kim, S.; Ha, T. Curcumin-induced suppression of adipogenic differentiation is accompanied by activation of Wnt/beta-catenin signaling. Am. J. Physiol. Cell Physiol. 2010, 298, C1510-6. [Google Scholar] [CrossRef] [PubMed]
  62. Zhang, X.; Liu, J.; Pang, X.; Zhao, J.; Xu, S. Curcumin Suppresses Aldosterone-Induced CRP Generation in Rat Vascular Smooth Muscle Cells via Interfering with the ROS-ERK1/2 Signaling Pathway. Evid. Based. Complement. Altern. Med. 2020, 2020, 3245653. [Google Scholar] [CrossRef]
  63. Wu, T.; Xiang, Y.; Lv, Y.; Li, D.; Yu, L.; Guo, R. miR-590-3p mediates the protective effect of Curcumin on injured endothelial cells induced by angiotensin II. Am. J. Transl. Res. 2017, 9, 289–300. [Google Scholar] [PubMed]
  64. Ramaswami, G.; Chai, H.; Yao, Q.; Lin, P.H.; Lumsden, A.B.; Chen, C. Curcumin blocks homocysteine-induced endothelial dysfunction in porcine coronary arteries. J. Vasc. Surg. 2004, 40, 1216–1222. [Google Scholar] [CrossRef] [PubMed][Green Version]
  65. Montiel-Dávalos, A.; Silva Sánchez, G.J.; Huerta-García, E.; Rueda-Romero, C.; Soca Chafre, G.; Mitre-Aguilar, I.B.; Alfaro-Moreno, E.; Pedraza-Chaverri, J.; López-Marure, R. Curcumin inhibits activation induced by urban particulate material or titanium dioxide nanoparticles in primary human endothelial cells. PLoS ONE 2017, 12, e0188169. [Google Scholar] [CrossRef]
  66. Lee, S.E.; Park, H.R.; Jeon, S.; Han, D.; Park, Y.S. Curcumin Attenuates Acrolein-induced COX-2 Expression and Prostaglandin Production in Human Umbilical Vein Endothelial Cells. J. Lipid Atheroscler. 2020, 9, 184–194. [Google Scholar] [CrossRef]
  67. Lee, H.-S.; Lee, M.-J.; Kim, H.; Choi, S.-K.; Kim, J.-E.; Moon, H.-I.; Park, W.-H. Curcumin inhibits TNFalpha-induced lectin-like oxidised LDL receptor-1 (LOX-1) expression and suppresses the inflammatory response in human umbilical vein endothelial cells (HUVECs) by an antioxidant mechanism. J. Enzym. Inhib. Med. Chem. 2010, 25, 720–729. [Google Scholar] [CrossRef]
  68. Kim, D.-C.; Ku, S.-K.; Lee, W.; Bae, J.-S. Barrier protective activities of Curcumin and its derivative. Inflamm. Res. Off. J. Eur. Histamine Res. Soc. 2012, 61, 437–444. [Google Scholar] [CrossRef]
  69. Kim, Y.S.; Ahn, Y.; Hong, M.H.; Joo, S.Y.; Kim, K.H.; Sohn, I.S.; Park, H.W.; Hong, Y.J.; Kim, J.H.; Kim, W.; et al. Curcumin attenuates inflammatory responses of TNF-alpha-stimulated human endothelial cells. J. Cardiovasc. Pharmacol. 2007, 50, 41–49. [Google Scholar] [CrossRef]
  70. Zhong, Y.; Feng, J.; Li, J.; Fan, Z. Curcumin prevents lipopolysaccharide-induced matrix metalloproteinase-2 activity via the Ras/MEK1/2 signaling pathway in rat vascular smooth muscle cells. Mol. Med. Rep. 2017, 16, 4315–4319. [Google Scholar] [CrossRef]
  71. Zhang, M.; Li, Y.; Xie, H.; Chen, J.; Liu, S. Curcumin inhibits proliferation, migration and neointimal formation of vascular smooth muscle via activating miR-22. Pharm. Biol. 2020, 58, 610–619. [Google Scholar] [CrossRef]
  72. Yuan, H.-Y.; Kuang, S.-Y.; Zheng, X.; Ling, H.-Y.; Yang, Y.-B.; Yan, P.-K.; Li, K.; Liao, D.-F. Curcumin inhibits cellular cholesterol accumulation by regulating SREBP-1/caveolin-1 signaling pathway in vascular smooth muscle cells. Acta Pharmacol. Sin. 2008, 29, 555–563. [Google Scholar] [CrossRef][Green Version]
  73. Den Dekker, W.K.; Cheng, C.; Pasterkamp, G.; Duckers, H.J. Toll like receptor 4 in atherosclerosis and plaque destabilization. Atherosclerosis 2010, 209, 314–320. [Google Scholar] [CrossRef] [PubMed]
  74. Kim, K.-H.; Lee, E.N.; Park, J.K.; Lee, J.-R.; Kim, J.-H.; Choi, H.-J.; Kim, B.-S.; Lee, H.-W.; Lee, K.-S.; Yoon, S. Curcumin attenuates TNF-α-induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and proinflammatory cytokines in human endometriotic stromal cells. Phytother. Res. 2012, 26, 1037–1047. [Google Scholar] [CrossRef]
  75. Latz, E.; Xiao, T.S.; Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 2013, 13, 397–411. [Google Scholar] [CrossRef] [PubMed]
  76. Tian, K.; Ogura, S.; Little, P.J.; Xu, S.; Sawamura, T. Targeting LOX-1 in atherosclerosis and vasculopathy: Current knowledge and future perspectives. Ann. N.Y. Acad. Sci. 2019, 1443, 34–53. [Google Scholar] [CrossRef] [PubMed]
  77. Min, K.; Um, H.J.; Cho, K.-H.; Kwon, T.K. Curcumin inhibits oxLDL-induced CD36 expression and foam cell formation through the inhibition of p38 MAPK phosphorylation. Food Chem. Toxicol. Int. J. Publ. Br. Ind. Biol. Res. Assoc. 2013, 58, 77–85. [Google Scholar] [CrossRef]
  78. Tontonoz, P.; Nagy, L.; Alvarez, J.G.A.; Thomazy, V.A.; Evans, R.M. PPARγ Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL. Cell 1998, 93, 241–252. [Google Scholar] [CrossRef][Green Version]
  79. Chistiakov, D.A.; Bobryshev, Y.V.; Orekhov, A.N. Macrophage-mediated cholesterol handling in atherosclerosis. J. Cell. Mol. Med. 2016, 20, 17–28. [Google Scholar] [CrossRef][Green Version]
  80. Makowski, L.; Brittingham, K.C.; Reynolds, J.M.; Suttles, J.; Hotamisligil, G.S. The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. J. Biol. Chem. 2005, 280, 12888–12895. [Google Scholar] [CrossRef][Green Version]
  81. Wessel, J.; Topol, E.J.; Ji, M.; Meyer, J.; McCarthy, J.J. Replication of the association between the thrombospondin-4 A387P polymorphism and myocardial infarction. Am. Heart J. 2004, 147, 905–909. [Google Scholar]
  82. Changal, K.H.; Khan, M.S.; Bashir, R.; Sheikh, M.A. Curcumin Preparations Can Improve Flow-Mediated Dilation and Endothelial Function: A Meta-Analysis. Complement. Med. Res. 2020, 27, 272–281. [Google Scholar] [CrossRef]
  83. Li, X.; Lu, Y.; Sun, Y.; Zhang, Q. Effect of Curcumin on permeability of coronary artery and expression of related proteins in rat coronary atherosclerosis heart disease model. Int. J. Clin. Exp. Pathol. 2015, 8, 7247–7253. [Google Scholar]
  84. Gao, S.; Zhang, W.; Zhao, Q.; Zhou, J.; Wu, Y.; Liu, Y.; Yuan, Z.; Wang, L. Curcumin ameliorates atherosclerosis in apolipoprotein E deficient asthmatic mice by regulating the balance of Th2/Treg cells. Phytomedicine 2019, 52, 129–135. [Google Scholar] [CrossRef] [PubMed]
  85. Majeed, M.L.; Ghafil, F.A.; Fatima, G.; Hadi, N.R.; Mahdi, H.F. Anti-Atherosclerotic and Anti-Inflammatory Effects of Curcumin on Hypercholesterolemic Male Rabbits. Indian J. Clin. Biochem. 2021, 36, 74–80. [Google Scholar] [CrossRef]
  86. Amato, A.; Caldara, G.F.; Nuzzo, D.; Baldassano, S.; Picone, P.; Rizzo, M.; Mulè, F.; Di Carlo, M. NAFLD and atherosclerosis are prevented by a natural dietary supplement containing curcumin, silymarin, guggul, chlorogenic acid and inulin in mice fed a high-fat diet. Nutrients 2017, 9, 492. [Google Scholar] [CrossRef] [PubMed][Green Version]
  87. Coban, D.; Milenkovic, D.; Chanet, A.; Khallou-Laschet, J.; Sabbe, L.; Palagani, A.; Vanden Berghe, W.; Mazur, A.; Morand, C. Dietary curcumin inhibits atherosclerosis by affecting the expression of genes involved in leukocyte adhesion and transendothelial migration. Mol. Nutr. Food Res. 2012, 56, 1270–1281. [Google Scholar] [CrossRef]
  88. Ghosh, S.S.; Bie, J.; Wang, J.; Ghosh, S. Oral supplementation with non-absorbable antibiotics or Curcumin attenuates western diet-induced atherosclerosis and glucose intolerance in LDLR−/− mice–role of intestinal permeability and macrophage activation. PLoS ONE 2014, 9, e108577. [Google Scholar] [CrossRef][Green Version]
  89. Pan, Y.; Wang, Y.; Cai, L.; Cai, Y.; Hu, J.; Yu, C.; Li, J.; Feng, Z.; Yang, S.; Li, X.; et al. Inhibition of high glucose-induced inflammatory response and macrophage infiltration by a novel Curcumin derivative prevents renal injury in diabetic rats. Br. J. Pharmacol. 2012, 166, 1169–1182. [Google Scholar] [CrossRef][Green Version]
  90. Jin, S.; Hong, J.H.; Jung, S.H.; Cho, K.H. Turmeric and laurel aqueous extracts exhibit in vitro anti-atherosclerotic activity and in vivo hypolipidemic effects in a zebrafish model. J. Med. Food 2011, 14, 247–256. [Google Scholar] [CrossRef]
  91. Shin, S.K.; Ha, T.Y.; McGregor, R.A.; Choi, M.S. Long-term Curcumin administration protects against atherosclerosis via hepatic regulation of lipoprotein cholesterol metabolism. Mol. Nutr. Food Res. 2011, 55, 1829–1840. [Google Scholar] [CrossRef] [PubMed]
  92. Wan, Q.; Liu, Z.Y.; Yang, Y.P.; Liu, S.M. Effect of Curcumin on inhibiting atherogenesis by down-regulating lipocalin-2 expression in apolipoprotein E knockout mice. Bio-Med. Mater. Eng. 2016, 27, 577–587. [Google Scholar] [CrossRef]
  93. Zheng, B.; Yang, L.; Wen, C.; Huang, X.; Xu, C.; Lee, K.H.; Xu, J. Curcumin analog L3 alleviates diabetic atherosclerosis by multiple effects. Eur. J. Pharmacol. 2016, 775, 22–34. [Google Scholar] [CrossRef]
  94. Zou, J.; Zhang, S.; Li, P.; Zheng, X.; Feng, D. Supplementation with Curcumin inhibits intestinal cholesterol absorption and prevents atherosclerosis in high-fat diet–fed apolipoprotein E knockout mice. Nutr. Res. 2018, 56, 32–40. [Google Scholar] [CrossRef] [PubMed]
  95. Panahi, Y.; Khalili, N.; Sahebi, E.; Namazi, S.; Reiner, Ž.; Majeed, M.; Sahebkar, A. Curcuminoids modify lipid profile in type 2 diabetes mellitus: A randomized controlled trial. Complementary Ther. Med. 2017, 33, 1–5. [Google Scholar] [CrossRef] [PubMed]
  96. Panahi, Y.; Kianpour, P.; Mohtashami, R.; Jafari, R.; Simental-Mendía, L.E.; Sahebkar, A. Curcumin lowers serum lipids and uric acid in subjects with nonalcoholic fatty liver disease: A randomized controlled trial. J. Cardiovasc. Pharmacol. 2016, 68, 223–229. [Google Scholar] [CrossRef]
  97. Ramırez-Boscá, A.; Soler, A.; Carrion, M.A.; Dıaz-Alperi, J.; Bernd, A.; Quintanilla, C.; Almagro, E.Q.; Miquel, J. An hydroalcoholic extract of Curcuma longa lowers the apo B/apo A ratio: Implications for atherogenesis prevention. Mech. Ageing Dev. 2000, 119, 41–47. [Google Scholar] [CrossRef]
  98. Wongcharoen, W.; Jai-Aue, S.; Phrommintikul, A.; Nawarawong, W.; Woragidpoonpol, S.; Tepsuwan, T.; Sukonthasarn, A.; Apaijai, N.; Chattipakorn, N. Effects of curcuminoids on frequency of acute myocardial infarction after coronary artery bypass grafting. Am. J. Cardiol. 2012, 110, 40–44. [Google Scholar] [CrossRef] [PubMed]
  99. Funamoto, M.; Sunagawa, Y.; Katanasaka, Y.; Miyazaki, Y.; Imaizumi, A.; Kakeya, H.; Yamakage, H.; Satoh-Asahara, N.; Komiyama, M.; Wada, H.; et al. Highly absorptive Curcumin reduces serum atherosclerotic low-density lipoprotein levels in patients with mild COPD. Int. J. Chronic Obstr. Pulm. Dis. 2016, 11, 2029. [Google Scholar]
  100. DiSilvestro, R.A.; Joseph, E.; Zhao, S.; Bomser, J. Diverse effects of a low dose supplement of lipidated Curcumin in healthy middle aged people. Nutr. J. 2012, 11, 1–8. [Google Scholar] [CrossRef][Green Version]
  101. Oliver, J.M.; Stoner, L.; Rowlands, D.S.; Caldwell, A.R.; Sanders, E.; Kreutzer, A.; Mitchell, J.B.; Purpura, M.; Jäger, R. Novel form of Curcumin improves endothelial function in young, healthy individuals: A double-blind placebo controlled study. J. Nutr. Metab. 2016, 2016, 1089653. [Google Scholar] [CrossRef][Green Version]
  102. Campbell, M.S.; Berrones, A.J.; Krishnakumar, I.M.; Charnigo, R.J.; Westgate, P.M.; Fleenor, B.S. Responsiveness to Curcumin intervention is associated with reduced aortic stiffness in young, obese men with higher initial stiffness. J. Funct. Foods 2017, 29, 154–160. [Google Scholar] [CrossRef]
  103. Zhou, Y.; Little, P.J.; Xu, S.; Kamato, D. Curcumin Inhibits Lysophosphatidic Acid Mediated MCP-1 Expression via Blocking ROCK Signalling. Molecules 2021, 26, 2320. [Google Scholar] [CrossRef] [PubMed]
  104. Helli, B.; Gerami, H.; Kavianpour, M.; Heybar, H.; Hosseini, S.K.; Haghighian, H.K. Curcumin Nanomicelle Improves Lipid Profile, Stress Oxidative Factors and Inflammatory Markers in Patients Undergoing Coronary Elective Angioplasty; A Randomized Clinical Trial. Endocr. Metab. Immune Disord. Drug Targets 2021. [Google Scholar] [CrossRef] [PubMed]
  105. Li, L.; Zhang, X.; Pi, C.; Yang, H.; Zheng, X.; Zhao, L.; Wei, Y. Review of Curcumin Physicochemical Targeting Delivery System. Int. J. Nanomed. 2020, 15, 9799–9821. [Google Scholar] [CrossRef]
  106. Pechanova, O.; Dayar, E.; Cebova, M. Therapeutic Potential of Polyphenols-Loaded Polymeric Nanoparticles in Cardiovascular System. Molecules 2020, 25, 3322. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Pharmacological effects and mechanism of action of curcumin in atherosclerosis.
Figure 1. Pharmacological effects and mechanism of action of curcumin in atherosclerosis.
Molecules 26 04036 g001
Table 1. In vitro evidence supporting the therapeutic potential of curcumin against atherosclerosis.
Table 1. In vitro evidence supporting the therapeutic potential of curcumin against atherosclerosis.
Experimental ModelConcentration UsedOutcomes and Possible Mechanisms of ActionReferences
U937 monocytes0.01–1 µM
Inhibit lipid peroxidation and inflammatory cytokine production under high glucose stimulated conditions
HMEC-1 cells0.1–10 μM
Reduce cell migration and viability and repress MMP-2, MMP-9, and VEGF expression
Upregulate miR-126 expression and inhibit PI3K/AKT and JAK2/STAT5 signal transduction
ANA-1 mouse macrophage cell line5–25 μM
Decrease THBS-4 expression as induced by oxLDL
RAW 264.7 macrophages
Inhibit foam cell formation and CD36 expression level via blocking p38 MAPK phosphorylation
H9c2 rat cardiac myoblasts5–40 μM
Activate p38-MAPK and JNK signaling pathways
Promote apoptosis by chromatin condensation
Human monocytic THP-1 cells7.5–30 μM
Inhibit M1 macrophage polarization and cytokine production (IL-6, IL-12B, and TNF-α) and decrease TLR-4 expression
Inhibit ERK, JNK, p38, and NF-kB phosphorylation, exerting anti-inflammatory and anti-atherosclerotic activity
Human monocytic THP-1 cells5–20 μM
Reduce the influx of oxLDL in THP-1 cells
Suppress CD36 and aP2 expression
RAW264.7 macrophage6.25 and 12.5 μM
Increase cholesterol efflux via Apo-A1 and HDL in macrophages
Reduce oxLDL-induced cytokine production as well as M1 macrophage apoptosis
Upregulate CD36 and ABCA1 expression in M1 macrophages
Ba/F3 cells10–20 μM
Inhibit TLR4 dimerization at the receptor level
Inhibit the activation of MyD88 and TRIF-dependent pathways, thereby blocking NF-κB and IRF3 signaling
RAW264.7 macrophage6.25–25 μM
Inhibit the expression of M1 macrophage markers (i.e., iNOS, IL-1b, IL-6, and MCP-1) and upregulate IKBα expression
RAW264.7 macrophage6.25–50 μM
Upregulate the expression of M2 markers such as MMR, Arg-1, and PPAR-, as well as macrophage M2 polarization via IL-4 and/or IL-13 secretion.
RAW264.7 macrophage6.25, and 25 nM
Repress titanium (Ti) particle-induced inflammation via modulating macrophage M1 to M2 polarization
RAW264.7 macrophage8–128 μM
Inhibit lipid accumulation and the production of MCP-1, TNF-α, and IL-6
Mouse peritoneal macrophages10–50 μM
Reduce TLR4 expression and inhibit NF-κB activation
Human monocytic THP-1 cells20–40 μM
Inhibit HIF-1α-induced apoptosis and inflammation of macrophages via ERK signaling pathway
Bovine aortic endothelial cells (BAECs)5–15 μM
Inhibit the expression of ET-1mRNA in BAECs, which may influence the formation of atherosclerotic plaques
RAW264.7 macrophage0.1–30 μM
Repress IL-1β, IL-6, and TNF-α production
Human monocytic THP-1 cells0–50 μM
Attenuate MMP-9 and EMMPRIN expression via downregulation of NF-κB and p38 MAPK signaling
Human monocytic THP-1 cells0 to 100 μM
Inhibit MMP-9 and EMMPRIN expression via inhibiting AMPK and PKC pathway
Human monocytic THP-1 cells10−20 μM
Inhibit the PKC-δ/NADPH oxidase/ROS signaling and suppress matrix invasion
Human monocytic THP-1 cells0–50 μM
Suppress TLR4/MyD88/NF-κB and P2X7R signaling and inhibit inflammasome activation
THP1-derived macrophage foam cells0–80 μM
Promote cholesterol efflux via increased ABCA1 expression via AMPK-SIRT1-LXRa signaling pathway
Human monocytic THP-1 cells5.0 µg/mL
Increase macrophage apoptosis, thus indicating a novel son o-dynamic therapy for atherosclerosis
VSMCs5–30 μM
Suppress oxLDL induced MCP-1 expression via p38 MAPK and NF-κB signaling
H9c2 embryonic rat heart derived cells5–15 μM
Enhance DOX-induced cells apoptosis via Bcl-2 repression and increasing expression of caspase-8 and -9
VSMCs5–30 μM
Decrease the expression/level of MCP-1, TNF-α, NO, and ROS production
Suppress TLR4 activation and inhibit ERK1/2 and p38 MAPK phosphorylation
RAW264.7 macrophage0–40 μM
Inhibit MCP-1 production via the JNK and NK-κB signaling
Enhance cholesterol efflux via activating the LXR-α, ABCA1 and SR-BI pathway
3T3-L1 fibroblast cells0–30 μM
Inhibit MAPK phosphorylation by using Wnt/β-catenin signaling, which leads to 3T3-L1 cell differentiation into adipocytes
VSMCs1.25–5 μM
Inhibit CRP protein production by modulating ROS-ERK1/2 signaling
Endothelial cells10−5 M
Inhibit CD40 expression and inflammatory activity via miR-590-3p-dependent pathway
Cultured porcine coronary artery rings5 μM
Block superoxide anion production mediated by eNOS downregulation and reverse endothelial dysfunction
HUVEC cells1, 10,100 μM
Reduce E- and P-selectins expression and monocytes adhesion induced by PM10 (3 μg/cm2) and TiO2-NPs (10 μg/cm2)
Attenuate oxidative stress activation induced by PM10 particles and TiO2-NPs in endothelial cells
HUVEC cells25 μM
Inhibit COX-2 expression and prostaglandin production
Inhibit phosphorylation of PKC, p38 MAPK, and cAMP response triggering COX-2 expression
HUVEC cells1–25 μM
Suppress the expression profile of ROS species, LOX-1 receptor, and adhesion molecules (VCAM-1 and ICAM-1)
Inhibit IκBα degradation and NFκB nuclear translocation
HUVEC cells2.5–100 μM
Decrease TLR2 and TLR4 mediated inflammatory response
Inhibit adhesion molecules expression that reconcile monocyte adhesion and endothelial migration
HUVEC cells3–30 μM
Inhibit NF-κB activation via TNF-α
Suppress intracellular ROS production, monocyte adhesion, and JNK, p38, and STAT-3 phosphorylation
Attenuate expression profile of ICAM-1, MCP-1, and IL -8 at both mRNA and protein levels
VSMCs20–40 μM
Diminish phosphorylation of p-RhoA/p-MEK1/2 and NF-κB signaling
Activate miR-22/SP1 signaling pathway and prevent proliferation and migration of VSMCs
VSMCs12.5–50 μM
Inhibit cholesterol accumulation via activating caveolin-1 expression that in turn negatively regulates SREBP-1 and prevents nuclear translocation
HUVEC cells0.5–2 μM
Inhibit HCMV replication and proliferation
Reduce intracellular ROS production and diminish inflammatory cytokine production
Downregulate HMGB1-TLR-NF-κB signaling
VSMCs10–20 μM
Reduce NO production by inhibiting IL-6 and TNF-expression
Upregulate PPAR-γ activity and attenuate VSMC proliferation
VSMCs20 μM
Inhibit cell migration by negatively regulating NLRP3 expression via NF-κB -mediated response and reduce IL-1β concentration
HMEC-1, human micro-vascular endothelial; PARP, poly(ADP-ribose) polymerase;MMR, macrophage mannose receptor; Arg-1, arginase-1; HIF-1α, hypoxia- inducible factor 1α; TGF-β, transforming growth factor beta; AMPK, AMP-activated protein kinase; PKC, protein kinase C; DOX, doxorubicin; ET-1, endothelin-1; PAR-γ, proliferator-activated receptor γ; LXR-α, liver X receptor α; SR-BI, scavenger receptor class B type I; JAKs, Janus activated kinases; iNOS, inducible nitric oxide synthase; MyD88, myeloid differentiation factor 88; P2X7R, purinergic 2X7 receptor; PKC, protein kinase C; AD, aldosterone, CRP, C-reactive protein; HUVEC, human umbilical vein endothelial cells; LOX-1, lectin-like oxidized LDL receptor-1; TEM, trans-endothelial migration; HMGB1, high mobility group box-1; MEK 1/2, mitogen-activated protein kinase kinase 1/2; JNK-c, Jun N-terminal Kinase.
Table 2. In Vivoevaluation of the pharmacological properties of curcumin against atherosclerosis.
Table 2. In Vivoevaluation of the pharmacological properties of curcumin against atherosclerosis.
In Vivo Experimental ModelCurcumin ConcentrationOutcomes and Possible Mechanisms of ActionReferences
ApoE/ mice0.1% w/w
Downregulate TLR-4 expression
Reduce the expression of IL-1β, TNF-α, VCAM-1, and ICAM-1 and the activity of NF-κB
Inhibit macrophage infiltration, resulting in reduced atherosclerotic plaques and lesions development
Male New-Zealand rabbits1.66 mg/kg body weight
Reduce LDL propensity to lipid peroxidation
Decrease TC, TG, and phospholipids level in rabbits
New Zealand white male rabbits10 mg/kg/week
Reduce serum levels of TC, TG, and LDL-c
Decrease atherosclerotic lesions in the aortic arch
Ldlr/ mice500–1500 mg/kg
Reduce oxLDL uptake in HP-1 cells
Reduce the formation of fatty streaks and inhibit the expression of inflammatory cytokines, aP2, and CD36
Repress the progression of steatohepatosis
Male Wistar rats100 mg/(kg/d) curcumin
Inhibit the expression profile of MMP-9, CD40L, TNF-α, and CRP, thereby improving the permeability of coronary artery
ApoE/ mice200 mg/kg/d
Modulate T helper cell (Th2) and regulatory T cells (Tregs) to recover the formed atherosclerotic lesions and plaque
Male Rabbits0.2%
Reduce the expression of CRP, ICAM1, VCAM1, and PCSK9 gene expression
ApoE/LDLR—doubleknockout mice0.3 mg/perday
Reduce TC and TG levels in blood
Reduce atherosclerotic lesion area and size
Male C57BL/6J (B6) mice0.09 mg
Prevent liver fat accumulation and development of atherosclerotic lesions
Improve hyperlipidemia state
ApoE/ mice0.2%
Reduce leukocyte adhesion and trans endothelial migration
LDLR/ mice100 mg/kg
Improve intestinal function against glucose intolerance
Reduce aortic lesion area
Sprague-Dawley rats100 mg/kg body weight
Inhibit the production of IL-6, TNF-α, IL-8, MCP-1, glucose, and glycosylated hemoglobin (HbA1)
Sprague-Dawley rats0.2–5.0 mg/kg
Inhibit the production of TNF-α, IL-1β,and MCP-1
Zebrafish10% wt/wt
Inhibit hyper cholesterolemic state and improve antioxidant activity
ApoE/ mice15–25mg/kg/d
Reduce LDL-c, TC, and TG
Decrease atherosclerotic plaque formation in the aorta and reduce lipid deposition in the liver and inflammatory damage in the heart, lung, and kidney
ApoE/ mice10 mg/kg
Reduce the formation of microvessel plaques, inhibit MMP-2 and -9 activity and regulate LDL-c metabolism
LDLR/ mice0.02%w/w
Decrease TC, TG, LDL-C, and Apo-B levels
Increase plasma HDL-c and liver Apo A-I expression
Inhibit HMG-CoA reductase, ACAT1, and ACAT2 expression
ApoE/ mice40, 60, and 80 mg/kg/d curcumin
Reduce lipocalin-2 (LCN2) biomarkers of atherosclerosis, present an anti-hyperlipidemic effect, and inhibit the inflammatory response
Male ICR mice1–2mmol/kg/day
Ameliorate dyslipidemia and hyperglycemia, reduce oxidative stress, and enhance antioxidant activity
ApoE/ mice0.1% w/w
Reduce TC accumulation in the aortas
Lower LDL-c level and decrease intestinal cholesterol absorption
VCAM-1, vascular cell adhesion molecule; ICAM-1, intracellular adhesion molecule; MMP, matrix metalloproteinase; Apo A-I, apolipoprotein A-I; Apo B, apolipoprotein B; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-co-enzyme A reductase; ACAT, acyl-CoA/cholesterol acetyl transferases; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; CRP—creactive protein; MCP 1, monocyte chemoattractant protein 1.
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MDPI and ACS Style

Singh, L.; Sharma, S.; Xu, S.; Tewari, D.; Fang, J. Curcumin as a Natural Remedy for Atherosclerosis: A Pharmacological Review. Molecules 2021, 26, 4036.

AMA Style

Singh L, Sharma S, Xu S, Tewari D, Fang J. Curcumin as a Natural Remedy for Atherosclerosis: A Pharmacological Review. Molecules. 2021; 26(13):4036.

Chicago/Turabian Style

Singh, Laxman, Shikha Sharma, Suowen Xu, Devesh Tewari, and Jian Fang. 2021. "Curcumin as a Natural Remedy for Atherosclerosis: A Pharmacological Review" Molecules 26, no. 13: 4036.

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