Search Results (425)

Aortic aneurysms and dissections are devastating vascular diseases with high mortality, yet no pharmacological therapy has proven effective in halting growth or preventing rupture. Surgical and endovascular repair remain the only treatment options for advanced disease. Animal models have been indispensable in defining mechanisms and testing candidate therapies, but the diversity of protocols, strain-dependent variability, and heterogeneous endpoints complicate interpretation and translation. This review provides an update focused on how to match models to specific research questions. We critically compare commonly used abdominal aortic aneurysm (AAA) models (angiotensin II ± hyperlipidemia, elastase, calcium chloride, β-aminopropionitrile BAPN hybrids, and mineralocorticoid agonist/fludrocortisone models) with thoracic aortopathy and dissection models (BAPN alone or with AngII, genetic models including Marfan and smooth muscle contractile mutations, and AngII + TGF-β blockade). We highlight practical considerations on segment specificity, rupture incidence, lipid dependence, comorbidities, and outcome measurement, with emphasis on rigor and reporting standards. A translational thread on platelet–intraluminal thrombus biology, including the emerging biomarker and therapeutic targets such as glycoprotein VI (GPVI), is integrated across models. We offer a decision grid and rigor checklist to harmonize model use, enhance reproducibility, and accelerate translation. Full article

This study aimed to identify novel angiotensin-converting enzyme (ACE)-inhibitory peptides from royal jelly proteins (RJPs) by integrating in silico digestion, virtual screening, and in vitro evaluation. Three major royal jelly proteins (MRJP1-3) were subjected to in silico digestion using 16 enzymatic systems, yielding 1411 unique peptides. Virtual screening based on predicted bioactivity, toxicity, water solubility, and ADMET profiles resulted in the selection of 27 candidate peptides. Molecular docking revealed strong binding affinities for these peptides compared with the positive control captopril, among which PYPDWSFAK and RPYPDWSF exhibited potent ACE-inhibitory activity, with IC₅₀ values of 110 ± 1.02 μmol/L and 204 ± 0.61 μmol/L, respectively. Kinetic analysis indicated that PYPDWSFAK acts as a mixed-type ACE inhibitor. Docking visualization demonstrated that PYPDWSFAK forms multiple hydrogen bonds with key residues in the ACE active pocket and directly coordinates with the catalytic Zn²⁺ ion. Cellular assays showed that PYPDWSFAK was non-cytotoxic, suppressed Ang II–induced endothelial cell migration, restored NO and ET-1 balance, and enhanced SOD and GSH-Px activities. Overall, this study enriches the repertoire of ACE-inhibitory peptides derived from royal jelly proteins. Furthermore, PYPDWSFAK is identified as a promising ACE-inhibitory peptide with potential for incorporation into natural antihypertensive ingredients or functional foods. Full article

The role of hepatic stellate cells (HSCs) in the development of liver fibrosis and portal hypertension has already been largely clarified. Activation of HSCs might lead to self-increased proliferation and enhanced contractile activity, causing their transdifferentiation into myofibroblasts (activated HSCs), which drive the release of proinflammatory mediators, collagen, proteoglycans, and other extracellular matrix components, responsible for liver fibrosis and portal hypertension development. A possible mechanism for the pathophysiological role of HSCs in liver fibrosis might be autophagy, which breaks down the lipid droplets in quiescent HSCs, releasing fatty acids and providing the energy required for their activation into myofibroblasts. An ever-growing body of scientific evidence indicates that renin–angiotensin system (RAS) blockade can inhibit the evolution of fibrosis in patients with chronic liver diseases, and especially metabolic dysfunction-associated steatotic liver disease (MASLD), although the use of both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has not yet been officially identified as a potential fibrosis treatment. More recently, researchers have shown that overexpression of ACE2, induced by ACE inhibitor (ACEI) activity and leading to the degradation of angiotensin (ANG) II into ANG 1-7, inhibition of autophagy and consequent HSC activation, might prevent liver fibrosis development. This review aims to summarize recent pre-clinical studies and to identify a common thread underlying the latest scientific evidence in this field. Full article

Background: Hypertension and its complications are a major global health problem, and natural compounds with vasorelaxant effects are being investigated as potential antihypertensive agents. Objective: This study aimed to determine whether rosmarinic acid (RA) induces vasorelaxation in the rat thoracic aorta and to elucidate the underlying mechanisms. Methods: Isolated thoracic aortic rings, with or without endothelium, were precontracted with phenylephrine and subsequently exposed to cumulative concentrations of RA. The roles of endothelium-derived factors, potassium channels, and calcium signaling were evaluated using selective pharmacological inhibitors and activators. In addition, the involvement of the AMPK pathway, adenylate cyclase/cAMP pathway, PKC signaling, β-adrenergic receptors, muscarinic receptors, and angiotensin II in RA-induced vasorelaxation was investigated. Results: RA induced a concentration-dependent vasorelaxation in endothelium-intact thoracic aortic rings (p < 0.001; pD₂ = 7.67 ± 0.04). The vasorelaxant effect of RA was attenuated in endothelium-denuded vessels (pD2: 5.26 ± 0.18). The relaxation response was significantly attenuated by inhibitors of the PI3K/Akt/eNOS/NO/cGMP pathway and by blockers of BK_Ca, IK_Ca, and Kv potassium channels (p < 0.001). Furthermore, RA markedly inhibited both extracellular Ca²⁺ influx and intracellular Ca²⁺ release from the sarcoplasmic reticulum (p < 0.001). RA incubation also significantly reduced the contractions induced by angiotensin II (Ang II) and by the PKC activator PMA (p < 0.001). Other tested pathways had no significant influence on the vasorelaxant effect of RA (p > 0.05). Conclusions: These findings demonstrate that rosmarinic acid induces both endothelium-dependent and endothelium-independent vasorelaxation in the rat thoracic aorta through activation of the PI3K/Akt/eNOS/NO/cGMP pathway, opening of BK_Ca, IK_Ca, and Kv potassium channels, and suppression of Ca²⁺ mobilization. Additionally, inhibition of PKC- and angiotensin II-mediated vascular contraction contributes to RA-induced vasorelaxation. RA may therefore have therapeutic potential in the management of hypertension. Full article

Hypertension is a leading risk factor for cardiovascular disease and is associated with maladaptive cardiac remodeling, including hypertrophy and fibrosis. The roles of the receptor for advanced glycation end-products (RAGE) and the small GTPase Rap1a in angiotensin II (AngII)-induced remodeling remain unclear. This study examined how RAGE and Rap1a influence cardiac responses to AngII using wild-type (WT), RAGE knockout (RAGE KO), and Rap1a knockout (RapKO) mice. Cardiac structure and function were evaluated following AngII infusion. RapKO mice were protected from AngII-induced hypertrophy, whereas RAGE KO mice exhibited altered remodeling patterns. AngII consistently increased left ventricular wall thickness across all genotypes, indicating that structural remodeling is primarily treatment-driven. Measures of cardiac output and stroke volume also changed significantly with AngII, suggesting hemodynamic load as a key driver of functional adaptation. In contrast, diastolic functional parameters were genotype-dependent and remained stable with AngII exposure, demonstrating an intrinsic influence of RAGE and Rap1a on myocardial relaxation. These findings highlight distinct roles for RAGE and Rap1a in modulating hypertensive cardiac remodeling and may parallel human hypertensive heart disease, where increased RAGE and Rap1a expression associate with fibrosis and impaired relaxation. Targeting the crosstalk between the RAGE-AT1R axis and the cAMP-EPAC-Rap1a pathway may offer therapeutic potential to reduce adverse cardiac remodeling in hypertension. Full article

This study investigated the region-specific roles of transforming growth factor-β2 (TGF-β2) and angiotensin II (AngII) in extracellular matrix (ECM) remodeling and inflammatory responses within scleral tissues surrounding the optic nerve head (ONH), using primary human fibroblasts from posterior sclera, peripapillary sclera (ppScl), and fibroblast-like cells from lamina cribrosa (LC). In vivo validation was performed in a chronic ocular hypertension rat model. Fibrotic and inflammatory markers were analyzed by Western blotting, quantitative PCR, and immunocytochemistry following TGF-β2 or AngII stimulation, and in vivo effects were assessed after subtenon injection of pathway-specific inhibitors. TGF-β2 induced robust upregulation of α-smooth muscle actin, collagen type I, and fibronectin across all scleral regions, whereas AngII elicited regionally confined pro-inflammatory responses, particularly in the LC and ppScl, characterized by increased cyclooxygenase-2 expression. Inhibition of either pathway reduced ECM deposition in vivo, but only AngII blockade significantly attenuated glial activation and preserved retinal ganglion cells. These findings demonstrate that TGF-β2 predominantly drives fibrosis, while AngII promotes region-specific neuroinflammation, and that inflammation, rather than fibrosis alone, plays a critical role in glaucomatous neurodegeneration. Targeting both fibrotic and inflammatory mechanisms in a region-specific manner may offer improved neuroprotection in glaucoma. Full article

The deep fascia, traditionally regarded as a passive structural tissue, is now recognized as a metabolically and biologically active structure where biochemical signals and biomechanical forces interact to influence proprioception, pain, force transmission, and adaptation to mechanical load. In this study, the convergence point between Angiotensin II (Ang II) signaling via its receptor, Angiotensin type 1 receptor (AT1R), and the mechanosensor Yes-associated protein (YAP) was investigated in human fascial fibroblasts. The presence of angiotensin II (Ang II) receptors was confirmed in fibroblasts from the deep fascia, with the AT1 receptor being the most prevalent subtype. Short-term exposure to Ang II (15–30 min) caused YAP dephosphorylation and its translocation to the nucleus, indicating YAP activation. Notably, prolonged Ang II treatment (7 days) significantly increased the expression of fibrosis-related genes, including collagen types I and III (COL1A1, COL3A1), and hyaluronan binding protein 2 (HABP2). This gene expression was decreased by pretreatment with the AT1R antagonist irbesartan or the YAP inhibitor verteporfin. Additionally, Ang II promoted fibroblast proliferation/migration, key features of fibrotic progression, through AT1R-dependent pathways. These findings show that Ang II acts as both a biochemical and biomechanical signal in the deep fascia, activating YAP signaling and promoting fibrotic remodeling. Our results uncover a new Ang II–YAP pathway in fascial fibroblasts, offering potential targets for therapy in fibrosis and related conditions involving the deep fascia. Full article

Background/Objectives: Marine-derived bioactive peptides have been reported to possess blood pressure-regulatory effects. However, most studies have focused on the antihypertensive effects after single-dose administration, and research on long-term administration and its protective effects against hypertension-induced tissue damage remains limited. Therefore, this study aimed to investigate the long-term antihypertensive efficacy of IGTGIPGIW, a bioactive peptide derived from Hippocampus abdominalis (H. abdominalis), and its protective effects on hypertension-related tissue damage. Methods: To evaluate the blood pressure-regulatory effects, spontaneously hypertensive rats (SHRs) were orally administered a high-dose (50 mg/kg) IGTGIPGIW peptide group (H-IGTGIPGIW) for 8 weeks. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were monitored weekly. Serum levels of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and angiotensin-converting enzyme 2 (ACE2) were measured to assess the peptide’s regulatory effects on the renin–angiotensin system. Histological analyses of the aorta and heart tissues were performed to evaluate the protective effects against hypertension-induced tissue damage. Results: After 8 weeks of treatment, H-IGTGIPGIW significantly reduced SBP, DBP, and MAP compared with SHRs. Serum Ang II and ACE levels were significantly decreased, while ACE2 levels were significantly increased. Histological analyses demonstrated that IGTGIPGIW alleviated aortic wall thickening and reduced renal and cardiac tissue damage in SHR. Conclusions: IGTGIPGIW, a bioactive peptide derived from H. abdominalis, effectively regulated blood pressure by modulating serum Ang II, ACE, and ACE2 levels. Moreover, it protected against hypertension-induced aortic, renal and cardiac tissue damage, suggesting its potential as a functional ingredient for managing hypertension. Full article

Hypertension, a leading factor for cardiovascular diseases (CVD), is a particularly heavy burden in women during middle age, when cardioprotective hormones begin to decline. The abnormal handling of calcium (Ca²⁺) in vascular smooth muscle cells (VSMCs) leads to increased vasoconstriction, remodeling, and altered arterial compliance during hypertension. The Spontaneously Hypertensive Rats (SHR) is a model of essential hypertension, and middle-aged females with hypertension represent a stage of disease where vascular dysfunction is prominent but understudied. Losartan, a widely prescribed angiotensin II (AngII) receptor (AT1R) blocker, exerts antihypertensive effects by affecting Ang II/Ca²⁺ signaling. However, whether it corrects the Ca²⁺ mishandling in the aorta of middle-aged female SHR has not been established. In this study, the thoracic aorta from 36-week-old female SHRs treated with losartan was assessed for Ca²⁺ mishandling using myography and biochemical assays. Meanwhile, biomechanical properties and stiffness were evaluated using Pulse Wave Velocity (PWV), Atomic Force Microscopy (AFM), and assessments of collagen and elastin contents. Compared with normotensive controls, SHR demonstrated disrupted Ca²⁺ handling, increased stiffness, and Extracellular Matrix (ECM) remodeling in middle-aged females. Treatment with losartan abrogated Ca²⁺ mishandling influx and efflux in the VSMC, decreased stiffness, and restored the aortic structural changes. These findings demonstrate that losartan abolishes Ca²⁺ mishandling and highlight a mechanistic role of AT1R blockade in restoring vascular function in the aorta of middle-aged females during hypertension. Full article

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase expressed in smooth muscle cells (SMCs), with emerging roles in regulating contraction. We hypothesize that PLK1 contributes to smooth muscle contractility in pudendal arteries (PA), small mesenteric arteries (SMA), and the corpus cavernosum (CC). Using male C57BL/6J mice, we assessed mRNA and protein expression of PLK1 in these tissues. In addition, the arteries and CC were mounted in myographs for isometric force measurement. We then investigated whether PLK1 regulates SMC contractility induced by phenylephrine (PE), U46619, and angiotensin II (Ang II) in arteries, and by PE, serotonin (5-HT), and electrical field stimulation (EFS; 1–16 Hz) in the CC, both in the presence and absence of the PLK1 inhibitor volasertib. PLK1 expression was confirmed in the SMA, PA, and CC by RT-qPCR or Western blotting. Notably, PLK1 inhibition significantly reduced Ang II-induced contraction in the PA and SMA and attenuated EFS-induced contraction at 2 and 4 Hz in the CC. In contrast, responses to PE, U46619, and 5-HT were unaffected by PLK1 inhibition. These results suggest that PLK1 selectively mediates contraction in response to Ang II and neurogenic stimuli. PLK1 may therefore represent a novel, stimulus-specific regulator of vascular and erectile smooth muscle contractility. Full article

Preeclampsia (PE) is characterized by maternal hypertension accompanied with multi-organ dysfunction, such as maternal hepatic and renal dysfunction. Abnormal placental conditions may play a key role in regulating maternal organ function by promoting systemic inflammation. This study aimed to test the hypothesis that placenta-derived secretions contribute to hepatic and renal injury through interorgan communication using a PE-like mouse model. Pregnant mice were infused with angiotensin II (Ang II) from gestational day (GD) 12 (GD1 defined as the day of plug detection). Ang II infusion induced maternal hypertension, as well as liver injury (elevated serum amyloid A [SAA] secretion and alanine aminotransferase levels) and kidney injury (tubular damage with KIM-1 protein expression and immune cell infiltration). Treatment with placental-conditioned medium (CM) from Ang II-infused mice, but not from the control mice, stimulated SAA expression in liver cells. On the other hand, the effects of placental-CM from both the control and Ang II groups on kidney tubular cells were comparable. These findings suggest that placenta-derived secretions in the Ang II-induced PE-like phenotype specifically promote excessive SAA production in the liver. Furthermore, SAA administration in pregnant mice did not cause tubular injury but did promote renal immune cell infiltration, indicating that elevated hepatic SAA levels may contribute to maternal kidney inflammation. Taken together, these results suggest the presence of an in vivo organ network involving the placenta, liver, and kidneys during pregnancy, where dysfunction in one organ may exacerbate the pathogenesis of PE. Full article

The imbalance of the renin–angiotensin system (RAS), characterized by the overactivation of the pro-tumor ACE/AngII/AT1R axis, is closely linked to tumor growth, angiogenesis, metastasis, and poor prognosis. Natural polyphenols, such as EGCG and resveratrol, exert anti-cancer effects by dual-regulating RAS: they inhibit the pro-tumor axis by blocking renin, ACE activity, and AT1R expression, while simultaneously activating the protective ACE2/Ang(1-7)/MasR axis. Furthermore, polyphenols and their autoxidation products (e.g., EAOP) modify thiol-containing transmembrane proteins (such as ADAM17 and integrins) and interact with RAS components, further disrupting oncogenic pathways (including MAPK and PI3K/Akt/mTOR) to induce apoptosis, suppress invasion, and reduce oxidative stress. Notably, EAOP exhibits stronger RAS-modulating efficacy than its parent polyphenols. However, challenges such as low bioavailability, insufficient targeting, and limited clinical evidence impede their application. This review provides a comprehensive overview of the anti-cancer mechanisms of polyphenols through RAS regulation, discusses the associated challenges, and proposes potential solutions (including nanodelivery and structural modification) and strategies to advance natural product-based adjuvant treatments. Full article

Background: Cardiorenal syndrome (CRS) reflects bidirectional heart–kidney injury whose mechanisms extend far beyond hemodynamics. High-throughput genomics and multi-omics now illuminate the molecular circuits that couple cardiac and renal dysfunction. Methods: We narratively synthesize animal and human studies leveraging transcriptomics, proteomics, peptidomics, metabolomics, and non-coding RNA profiling to map convergent pathways in CRS and to highlight biomarker and therapeutic implications. Results: Across acute and chronic CRS models, omics consistently converge on extracellular matrix (ECM) remodeling and fibrosis (e.g., FN1, POSTN, collagens), immune–inflammatory activation (IL-6 axis, macrophage/complement signatures), renin–angiotensin–aldosterone system hyperactivity, oxidative stress, and metabolic/mitochondrial derangements in both organs. Single-nucleus and bulk transcriptomes reveal tubular dedifferentiation after cardiac arrest-induced AKI and myocardial reprogramming with early CKD, while quantitative renal proteomics in heart failure demonstrates marked upregulation of ACE/Ang II and pro-fibrotic matricellular proteins despite near-normal filtration. Human translational data corroborate these signals: urinary peptidomics detects CRS-specific collagen fragments and protease activity, and circulating FN1/POSTN and selected microRNAs (notably miR-21) show diagnostic potential. Epigenetic and microRNA networks appear to integrate these axes, nominating targets such as anti-miR-21 and anti-fibrotic strategies; pathway-directed repurposing exemplifies dual-organ benefit. Conclusions: Genomics and multi-omics recast CRS as a systems disease driven by intertwined fibrosis, inflammation, neurohormonal and metabolic programs. We propose a translational framework that advances (i) composite biomarker panels combining injury, fibrosis, and regulatory RNAs; (ii) precision, pathway-guided therapies; and (iii) integrated, longitudinal multi-omics of well-phenotyped CRS cohorts to enable prediction and personalized intervention. Full article

Bromodomain and extraterminal domain (BET) proteins act as epigenetic regulators of gene transcription. BET inhibitors have shown therapeutic potential in various models of heart failure; however, their efficacy in atrial fibrillation (AF) remains incompletely understood. This study investigated the effects of the BET inhibitor JQ1 in a mice model of AF. Wild-type male C57BL/6 mice were randomized into four groups: control, JQ1 alone (50 mg/kg, intraperitoneal), angiotensin II (AngII; 1 μg/kg/min), and AngII plus JQ1. After 2 weeks, electrophysiological studies revealed that JQ1 significantly reduced AngII-induced AF inducibility and duration. It also attenuated left atrial enlargement, diastolic dysfunction, and cardiac fibrosis. Molecular analyses indicated that JQ1 suppressed the AngII-induced upregulation of pro-fibrotic genes and restored Sirt1 expression. Moreover, JQ1 also inhibited AngII-enhanced oxidized CaMKII and phosphorylated RyR2 levels. In HL-1 atrial cardiomyocytes, JQ1 improved calcium handling abnormalities, shortened prolonged action potential duration (APD), and restored mitochondrial respiration and adenosine triphosphate (ATP) production, all of which had been impaired by AngII. These findings suggest that BET inhibition by JQ1 mitigates structural and electrical remodeling associated with AF by attenuating atrial fibrosis, and by restoring calcium homeostasis, mitochondrial function, and Sirt1 expression. JQ1 may represent a novel therapeutic strategy for the prevention and treatment of AF. Full article

We evaluated the effects of fenofibrate (FF) in a SU5416/hypoxia model of pulmonary arterial hypertension (PAH) with a specific focus on its influence on the renin–angiotensin system (RAS). We assessed right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP), medial pulmonary artery wall thickening, right ventricular (RV) hypertrophy, systolic pulmonary artery pressure (SPAP), pulmonary artery effective elastance (PAEa), RV diastolic pressure (RVDP), RV developed pressure (RVDevP), right ventricular–pulmonary arterial coupling index (RVPAC), RV dp/dt max and dp/dt min. Levels of angiotensin II, angiotensin (1–7), angiotensin-converting enzyme 2 (ACE2), Bmpr2, Smad5 and nitrite (NO₂⁻) and nitrate (NO₃⁻) in the lung and RV were evaluated. The expression of AT1R, MAS receptors, and ACE2 in lung tissue was assessed. FF prevented the increase in RVSP, mPAP, RV hypertrophy, reduced pulmonary arterioles remodeling, and attenuated the rise in SPAP, mPAP, and PAEa. In the RV, it reduced RVDevP and prevented the decrease in dp/dt min, without affecting RVDP. RVPAC showed partial improvement. In lung tissue, FF decreased angiotensin II levels, the Ang II/Ang-(1–7) ratio, and reduced angiotensin II receptor type 1 (AT1R) expression, while preserving the receptor for the angiotensin-(1–7) (MAS) and ACE2. FF tended to restore Bmpr2/Smad5 expression. NO₂⁻ levels were preserved and tended to preserve (NO₃⁻) levels. In the RV, Ang-(1–7) increased, ACE2 was preserved, and NO₂⁻ and NO₃ levels were maintained. FF exerts protective effects in Su/Hx-induced PAH. Full article