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Special Issue "Pathomechanisms of Atherosclerosis. Part II"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 May 2020).

Special Issue Editor

Prof. Dr. Michael Henein
Website
Guest Editor
Department of Public Health and Clinical Medical and Heart Center, Umea University, 901 87 Umea, Sweden;
St George University London, UK
Interests: non-invasive cardiology; echocardiography; coronary artery disease imaging; carotid atherosclerosis; valve disease and heart failure
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous special issue "Pathomechanisms of Atherosclerosis. Part I".

With the recent globalisation of life style in many parts of the world, atheroscleosis has become a global disease with a significant health threat and economic burden, not only in the West, but now also Asia and Africa. Despite the well documented conventional risk factors for atherosclerosis, little is known about the major differences between geographical regions and whether the effect of those factors remains at a similar level of impact in all nations. This also raises the question about the exact pathomechanism of atherosclerosis and if it is uniform or may have different pathways between continents and countries. Furthermore, whether the pattern of gross pathology, e.g., thickened intima-media, plaque formation, calcification, etc., has become amenable to study and to accurately analyse, is not known; is it nation specific?

This Special Issue of IJMS searches for answers to some of the above-mentioned questions in an attempt to provide cardiology and vascular specialists with some answers that should lead to a better understanding of such a serious universal disease. We look forward to your contributions.

Prof. Dr. Michael Henein
Guest Editor

Manuscript Submission Information

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Keywords

  • Atherosclerosis
  • Coronary calcification
  • Arterial disease
  • Inflammation
  • Pathomechanism of atherosclerosis

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Published Papers (10 papers)

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Research

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Open AccessArticle
A Timing Effect of 17-β Estradiol on Atherosclerotic Lesion Development in Female ApoE−/− Mice
Int. J. Mol. Sci. 2020, 21(13), 4710; https://doi.org/10.3390/ijms21134710 - 01 Jul 2020
Abstract
Differences in size or composition of existing plaques at the initiation of estrogen (E2) therapy may underpin evidence of increased risk of atherosclerosis-associated clinical sequelae. We investigated whether E2 had divergent effects on actively-growing versus established-advanced atherosclerotic lesions. Eight weeks of subcutaneous bi-weekly [...] Read more.
Differences in size or composition of existing plaques at the initiation of estrogen (E2) therapy may underpin evidence of increased risk of atherosclerosis-associated clinical sequelae. We investigated whether E2 had divergent effects on actively-growing versus established-advanced atherosclerotic lesions. Eight weeks of subcutaneous bi-weekly injections of 3 µg/g 17β-estradiol (n = 18) or vehicle control (n = 22) were administered to female Apolipoprotein null-mice aged 25- or 45 weeks old. Histological assessment of lesion size within the brachiocephalic artery was conducted. Lesion composition was also assessed with acellular, calcification and fibrosis areas measured and other cellular features (intimal thickening, foam cells, lipid pools and cholesterol) scored (0–3) for severity. The comparison showed increased lesion size and calcified area with advancing age but no effect of E2. However, subtle changes in composition were observed following E2. Within the younger group, E2 increased intima thickening and acceleration of calcification. In the older group, E2 increased the thickness of the lesion cap. Therefore, this study shows different effects of E2 depending on the underlying stage of lesion development at the time of initiation of treatment. These divergent changes help explain the controversy of the adverse effects of E2 treatment in cardiovascular disease. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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Open AccessArticle
Sleep Duration, Lipid Profile and Insulin Resistance: Potential Role of Lipoprotein(a)
Int. J. Mol. Sci. 2020, 21(13), 4680; https://doi.org/10.3390/ijms21134680 - 30 Jun 2020
Abstract
Lipoprotein (a) (Lp(a)) is considered a genetic factor for cardiovascular disease playing an important role in atherogenesis and thrombosis, but the evidence about its association with sleep duration is controversial. We evaluated the relation between self-reported sleep duration and Lp(a). Among 1600 participants [...] Read more.
Lipoprotein (a) (Lp(a)) is considered a genetic factor for cardiovascular disease playing an important role in atherogenesis and thrombosis, but the evidence about its association with sleep duration is controversial. We evaluated the relation between self-reported sleep duration and Lp(a). Among 1600 participants of the population-based sample, we selected 1427 subjects without previously known cardiovascular events, who answered the questions about their sleep duration; had valid lipid profile results (total cholesterol, low- and high-density lipoproteins, Lp(a), apolipoprotein AI (ApoAI), ApoB, and ApoB/ApoAI); and did not take lipid-lowering drugs (mean age 46 ± 12 years). We performed a structured interview, which included questions about lifestyle, medical history, complaints, and sleep duration (How long have you been sleeping per night during the last month?). Sleep duration was classified as follows: <6 h/night—short, 6–9 h/night—normal, and ≥10 h/night—long. Overall, 73 respondents (5.2%) were short-sleepers and 69 (4.8%) long-sleepers. Males were slightly more prevalent among short-sleepers. The groups matched by age, body mass index, blood pressure, diabetes mellitus, and hypertension rate. Short-sleepers had lower rates of high total cholesterol (≥5.0 mmol/L), lower Lp(a) levels and lower rates of increased Lp(a) ≥0.5 g/L, and higher insulin and insulin resistance (assessed by the homeostatic model assessment for insulin resistance (HOMA-IR)). ApoAI, ApoB, their ratio, and other lab tests were similar in the groups. The multinomial logistic regression demonstrated that only the short sleep duration was independently (odds ratio (OR) 0.29, 95% confidence interval (CI) (0.09–0.91), p = 0.033) associated with Lp(a) (χ2 = 41.58, p = 0.003). Other influencing factors were smoking and HOMA-IR. Such an association was not found for long-sleepers. In conclusion, a short-sleep duration is associated with Lp(a). The latter might mediate the higher insulin resistance and higher cardiometabolic risks in short-sleepers. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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Open AccessArticle
Heterozygous Ldlr-Deficient Hamster as a Model to Evaluate the Efficacy of PCSK9 Antibody in Hyperlipidemia and Atherosclerosis
Int. J. Mol. Sci. 2019, 20(23), 5936; https://doi.org/10.3390/ijms20235936 - 26 Nov 2019
Cited by 2
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis and atherogenesis. However, there are only limited rodent models, with a functional low-density lipoprotein receptor (LDLR) pathway and cholesteryl ester transfer protein (CETP) to evaluate the drug candidates targeting the [...] Read more.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis and atherogenesis. However, there are only limited rodent models, with a functional low-density lipoprotein receptor (LDLR) pathway and cholesteryl ester transfer protein (CETP) to evaluate the drug candidates targeting the PCSK9/LDLR pathway, that are translatable to humans. Here, by using our recently generated LDLR heterozygote (Ldlr+/−) hamster model with functional LDLR pathway and CETP function, we seek to evaluate the effect of a PCSK9 antibody, evolocumab, on dyslipidemia and atherosclerosis compared with ezetimibe, an effective inhibitor of cholesterol absorption, as a positive therapeutic control. We show that the plasma levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were significantly increased in Ldlr+/− hamsters fed a high-fat high-cholesterol (HFHC) diet; therefore, areas of atherosclerotic lesion in the aorta were obviously increased and positively correlated with plasma LDL-C and TC. Circulating free PCSK9 was downregulated by the HFHC diet and was undetectable in the evolocumab treated group, as expected. Most importantly, either evolocumab or ezetimibe treatment prevented HFHC diet-induced hyperlipidemia and subsequent atherosclerotic plaque formation. The results indicate that Ldlr+/− hamsters fed an HFHC diet represent an ideal rodent model to evaluate drug candidates that affect LDLR pathways. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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Open AccessArticle
Calcium Phosphate Bions Cause Intimal Hyperplasia in Intact Aortas of Normolipidemic Rats through Endothelial Injury
Int. J. Mol. Sci. 2019, 20(22), 5728; https://doi.org/10.3390/ijms20225728 - 15 Nov 2019
Cited by 2
Abstract
Calcium phosphate bions (CPBs) are formed under blood supersaturation with calcium and phosphate owing to the mineral chaperone fetuin-A and representing mineralo-organic particles consisting of bioapatite and multiple serum proteins. While protecting the arteries from a rapid medial calcification, CPBs cause endothelial injury [...] Read more.
Calcium phosphate bions (CPBs) are formed under blood supersaturation with calcium and phosphate owing to the mineral chaperone fetuin-A and representing mineralo-organic particles consisting of bioapatite and multiple serum proteins. While protecting the arteries from a rapid medial calcification, CPBs cause endothelial injury and aggravate intimal hyperplasia in balloon-injured rat aortas. Here, we asked whether CPBs induce intimal hyperplasia in intact rat arteries in the absence of cardiovascular risk factors. Normolipidemic Wistar rats were subjected to regular (once/thrice per week over 5 weeks) tail vein injections of either spherical (CPB-S) or needle-shaped CPBs (CPB-N), magnesium phosphate bions (MPBs), or physiological saline (n = 5 per group). Neointima was revealed in 3/10 and 4/10 rats which received CPB-S or CPB-N, respectively, regardless of the injection regimen or blood flow pattern in the aortic segments. In contrast, none of the rats treated with MPBs or physiological saline had intimal hyperplasia. The animals also did not display signs of liver or spleen injury as well as extraskeletal calcium deposits. Serum alanine/aspartate transaminases, interleukin-1β, MCP-1/CCL2, C-reactive protein, and ceruloplasmin levels did not differ among the groups. Hence, CPBs may provoke intimal hyperplasia via direct endothelial injury regardless of their shape or type of blood flow. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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Open AccessArticle
Carvedilol Ameliorates Experimental Atherosclerosis by Regulating Cholesterol Efflux and Exosome Functions
Int. J. Mol. Sci. 2019, 20(20), 5202; https://doi.org/10.3390/ijms20205202 - 20 Oct 2019
Cited by 1
Abstract
Carvedilol (Cav), a nonselective β-blocker with α1 adrenoceptor blocking effect, has been used as a standard therapy for coronary artery disease. This study investigated the effects of Cav on exosome expression and function, ATP-binding cassette transporter A1 (ABCA1) expression, and cholesterol efflux that [...] Read more.
Carvedilol (Cav), a nonselective β-blocker with α1 adrenoceptor blocking effect, has been used as a standard therapy for coronary artery disease. This study investigated the effects of Cav on exosome expression and function, ATP-binding cassette transporter A1 (ABCA1) expression, and cholesterol efflux that are relevant to the process of atherosclerosis. Human monocytic (THP-1) cell line and human hepatic (Huh-7) cells were treated with Cav, and cholesterol efflux was measured. Exosomes from cell culture medium or mice serum were isolated using glycan-coated recognition beads. Low-density lipoprotein receptor knockout (ldlr−/−) mice were fed with high-fat diet and treated with Cav. Cav accentuated cholesterol efflux and enhanced the expressions of ABCA1 protein and mRNA in both THP-1 and Huh-7 cells. In addition, Cav increased expression and function of exosomal ABCA1 in THP-1 macrophage exosomes. The mechanisms were associated with inhibition of nuclear factor-κB (NF-κB) and protein kinase B (Akt). In hypercholesterolemic ldlr−/− mice, Cav enhanced serum exosomal ABCA1 expression and suppressed atherosclerosis by inhibiting lipid deposition and macrophage accumulation. Cav halts atherosclerosis by enhancing cholesterol efflux and increasing ABCA1 expression in macrophages and in exosomes, possibly through NF-κB and Akt signaling, which provides mechanistic insights regarding the beneficial effects of Cav on atherosclerotic cardiovascular disease. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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Open AccessCommunication
Dietary Cholesterol Is Highly Associated with Severity of Hyperlipidemia and Atherosclerotic Lesions in Heterozygous LDLR-Deficient Hamsters
Int. J. Mol. Sci. 2019, 20(14), 3515; https://doi.org/10.3390/ijms20143515 - 18 Jul 2019
Cited by 3
Abstract
Objective: Familial hypercholesterolemia (FH) is a dominant inherited disease caused mainly by low-density lipoprotein receptor (LDLR) gene mutations. To different extents, both heterozygous and homozygous FH patients develop premature coronary heart disease (CHD). However, most of the experimental animal models with LDLR deficiency [...] Read more.
Objective: Familial hypercholesterolemia (FH) is a dominant inherited disease caused mainly by low-density lipoprotein receptor (LDLR) gene mutations. To different extents, both heterozygous and homozygous FH patients develop premature coronary heart disease (CHD). However, most of the experimental animal models with LDLR deficiency could not fully recapitulate FH because they develop hyperlipidemia and atherosclerosis only in homozygous, but not in heterozygous, form. In the current study, we investigated the responsiveness of the LDLR+/− hamster to dietary cholesterol and whether plasma cholesterol levels were positively associated with the severity of atherosclerosis. Approach and Methods: wild type WT and LDLR+/− hamsters were fed a high fat diet with different cholesterol contents (HCHF) for 12 or 16 weeks. Plasma lipids, (apo)lipoproteins, and atherosclerosis in both the aorta and coronary arteries were analyzed. After a HCHF diet challenge, the levels of total cholesterol (TC) in WT and LDLR+/− hamsters were significantly elevated, but the latter showed a more pronounced lipoprotein profile, with higher cholesterol levels that were positively correlated with dietary cholesterol contents. The LDLR+/− hamsters also showed accelerated atherosclerotic lesions in the aorta and coronary arteries, whereas only mild aortic lesions were observed in WT hamsters. Conclusions: Our findings demonstrate that, unlike other rodent animals, the levels of plasma cholesterol in hamsters can be significantly modulated by the intervention of dietary cholesterol, which were closely associated with severity of atherosclerosis in LDLR+/− hamsters, suggesting that the LDLR+/− hamster is an ideal animal model for FH and has great potential in the study of FH and atherosclerosis-related CHD. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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Open AccessArticle
Legumain Promotes Atherosclerotic Vascular Remodeling
Int. J. Mol. Sci. 2019, 20(9), 2195; https://doi.org/10.3390/ijms20092195 - 04 May 2019
Cited by 4
Abstract
Legumain, a recently discovered cysteine protease, is increased in both carotid plaques and plasma of patients with carotid atherosclerosis. Legumain increases the migration of human monocytes and human umbilical vein endothelial cells (HUVECs). However, the causal relationship between legumain and atherosclerosis formation is [...] Read more.
Legumain, a recently discovered cysteine protease, is increased in both carotid plaques and plasma of patients with carotid atherosclerosis. Legumain increases the migration of human monocytes and human umbilical vein endothelial cells (HUVECs). However, the causal relationship between legumain and atherosclerosis formation is not clear. We assessed the expression of legumain in aortic atheromatous plaques and after wire-injury-induced femoral artery neointimal thickening and investigated the effect of chronic legumain infusion on atherogenesis in Apoe−/− mice. We also investigated the associated cellular and molecular mechanisms in vitro, by assessing the effects of legumain on inflammatory responses in HUVECs and THP-1 monocyte-derived macrophages; macrophage foam cell formation; and migration, proliferation, and extracellular matrix protein expression in human aortic smooth muscle cells (HASMCs). Legumain was expressed at high levels in atheromatous plaques and wire injury-induced neointimal lesions in Apoe−/− mice. Legumain was also expressed abundantly in THP-1 monocytes, THP-1 monocyte-derived macrophages, HASMCs, and HUVECs. Legumain suppressed lipopolysaccharide-induced mRNA expression of vascular cell adhesion molecule-1 (VCAM1), but potentiated the expression of interleukin-6 (IL6) and E-selectin (SELE) in HUVECs. Legumain enhanced the inflammatory M1 phenotype and oxidized low-density lipoprotein-induced foam cell formation in macrophages. Legumain did not alter the proliferation or apoptosis of HASMCs, but it increased their migration. Moreover, legumain increased the expression of collagen-3, fibronectin, and elastin, but not collagen-1, in HASMCs. Chronic infusion of legumain into Apoe−/− mice potentiated the development of atherosclerotic lesions, accompanied by vascular remodeling, an increase in the number of macrophages and ASMCs, and increased collagen-3 expression in plaques. Our study provides the first evidence that legumain contributes to the induction of atherosclerotic vascular remodeling. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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Open AccessArticle
Molecular Imaging of Vascular Calcification with 18F-Sodium-Fluoride in Patients Infected with Human Immunodeficiency Virus
Int. J. Mol. Sci. 2019, 20(5), 1183; https://doi.org/10.3390/ijms20051183 - 08 Mar 2019
Cited by 1
Abstract
18F-Sodium Fluoride (NaF) accumulates in areas of active hydroxyapatite deposition and potentially unstable atherosclerotic plaques. We assessed the presence of atherosclerotic plaques in 50 adult patients with HIV (HIV+) who had undergone two cardiac computed tomography scans to measure coronary artery calcium [...] Read more.
18F-Sodium Fluoride (NaF) accumulates in areas of active hydroxyapatite deposition and potentially unstable atherosclerotic plaques. We assessed the presence of atherosclerotic plaques in 50 adult patients with HIV (HIV+) who had undergone two cardiac computed tomography scans to measure coronary artery calcium (CAC) progression. CAC and its progression are predictive of an unfavorable prognosis. Tracer uptake was quantified in six arterial territories: aortic arch, innominate carotid artery, right and left internal carotid arteries, left coronary (anterior descending and circumflex) and right coronary artery. Thirty-one patients showed CAC progression and 19 did not. At least one territory with high NaF uptake was observed in 150 (50%) of 300 arterial territories. High NaF uptake was detected more often in non-calcified than calcified areas (68% vs. 32%), and in patients without than in those with prior CAC progression (68% vs. 32%). There was no correlation between clinical and demographic variables and NaF uptake. In clinically stable HIV+ patients, half of the arterial territories showed a high NaF uptake, often in the absence of macroscopic calcification. NaF uptake at one time point did not correlate with prior progression of CAC. Prospective studies will demonstrate the prognostic significance of high NaF uptake in HIV+ patients. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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Open AccessArticle
Circulating Chemerin Levels, but not the RARRES2 Polymorphisms, Predict the Long-Term Outcome of Angiographically Confirmed Coronary Artery Disease
Int. J. Mol. Sci. 2019, 20(5), 1174; https://doi.org/10.3390/ijms20051174 - 07 Mar 2019
Cited by 2
Abstract
Chemerin, a novel adipokine, has been associated with metabolic, inflammatory, and atherosclerotic diseases. We aimed to determine the genetic basis of chemerin levels by conducting a genome-wide association study (GWAS) and to investigate the role of RARRES2 polymorphisms and circulating chemerin levels in [...] Read more.
Chemerin, a novel adipokine, has been associated with metabolic, inflammatory, and atherosclerotic diseases. We aimed to determine the genetic basis of chemerin levels by conducting a genome-wide association study (GWAS) and to investigate the role of RARRES2 polymorphisms and circulating chemerin levels in the long-term outcome of coronary artery disease (CAD). A total of 2197 participants from the Taiwan Biobank (TWB) were recruited for the GWAS analysis, and 481 patients with angiographically confirmed CAD were enrolled for long-term outcome analysis. One locus of genome-wide significance with a single independent association signal was identified in the GWAS for chemerin levels with the peak association at the RARRES2 gene promoter region polymorphism rs3735167 (p = 2.35 × 10−21). In the CAD population, borderline significance was noted between RARRES2 polymorphisms and chemerin levels, whereas high chemerin levels were associated with obesity, female sex, diabetes mellitus, hypertension, current smoking, high platelet and leukocyte counts, anemia, impaired renal function, high C-reactive protein (CRP) levels, and multi-vessel disease. Kaplan–Meier survival curves indicated that the patients with high chemerin and CRP levels, but not those with RARRES2 polymorphisms, had a lower survival rate and higher combined cerebral and cardiovascular event rates. Combined chemerin and CRP levels further revealed a stepwise increase in poor clinical outcomes from low- to high-risk subgroups. In conclusion, rs3735167 is the lead RARRES2 polymorphism for chemerin levels in Taiwanese. Chemerin levels, but not the rs3735167 genotypes, predicted the long-term outcome of CAD, especially when combined with CRP levels. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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Review

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Open AccessReview
Sleep, Autonomic Nervous Function and Atherosclerosis
Int. J. Mol. Sci. 2019, 20(4), 794; https://doi.org/10.3390/ijms20040794 - 13 Feb 2019
Cited by 4
Abstract
Behavioral and psychosocial factors related to development of cardiovascular disease have been gaining increased attention. Notably, sleep is considered to be one of the most important behavioral factors involved in progression of atherosclerosis and cardiovascular events, with autonomic nervous function a potential mechanism. [...] Read more.
Behavioral and psychosocial factors related to development of cardiovascular disease have been gaining increased attention. Notably, sleep is considered to be one of the most important behavioral factors involved in progression of atherosclerosis and cardiovascular events, with autonomic nervous function a potential mechanism. Several studies have shown associations of sleep and autonomic dysfunction with major surrogate markers of atherosclerosis, such as carotid intima-media thickness and arterial stiffness. Endocrinological, immunological, oxidative, inflammatory, and metabolic responses, as well as endothelial dysfunction may mediate the effects of the autonomic nervous system. For this review, we examined recent findings related to sleep, autonomic nervous dysfunction, and atherosclerosis, with the aim of understanding the involved pathophysiological mechanisms. Full article
(This article belongs to the Special Issue Pathomechanisms of Atherosclerosis. Part II)
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