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The chromogranin-secretogranin secretory proteins-granins-are acidic proteins localized in granules of endocrine cells and neurons. The chromogranin family includes chromogranins A (CgA) and B, as well as secretogranin II (once called chromogranin C). Members of this family undergo catalytic proteolysis to produce active peptides. The CgA-derived peptides vasostatin-1 and vasostatin-2, in particular, appear to protect against atherosclerosis, suppressing the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, as well as exerting vasodilatory effects by enhancing nitric oxide bioavailability. Vasostatin-1 also suppresses vasoconstriction and abnormal angiogenesis. Vasostatin-1 and vasostatin-2 may be novel therapeutic targets for atherosclerosis and coronary heart disease, also protecting the myocardium against ischaemic damage., Competing Interests: Conflict of interest: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The present study aimed to investigate the relationship between serum levels of secretory vimentin and coronary artery disease (CAD). The biological effect of secretory vimentin was ascertained by experiments., Methods: We analysed serum levels of secretory vimentin in CAD patients (n = 288) and non-CAD controls (n = 195) by ELISA. To evaluate the pro-inflammatory effects of secreted vimentin, the human aortic endothelial cells (HAECs) and human peripheral blood mononuclear cells (PBMCs) were treated with recombinant vimentin or saline. Intraperitoneal injection of vimentin (1 μg/each) or saline was performed every other day for 12 weeks in ApoE -/- mice for assessment of atherogenic effect., Results: Serum levels of secretory vimentin were significantly increased in CAD patients than in health controls (p < 0.05), and correlated with the number of diseased coronary arteries, Syntax and Gensini score (for all comparison, p < 0.01). Logistic regression analysis showed that vimentin level is an independent determinant of CAD. In experiments, recombinant vimentin protein enhanced the expression of adhesion molecules and inflammatory cytokines in both endothelial cells and macrophages. This protein also promoted macrophage-endothelial cells adhesion in vitro and the recruitment of leukocytes to mesenteric venules in C57BL/6 mice. Compared with saline, intraperitoneal injection of recombinant vimentin (1 μg/each) every other day induced atherogenesis in ApoE -/- mice at 12-weeks, with significant increase of inflammatory cytokine and adhesion molecules expression in aortic tissue (p < 0.05)., Conclusion: Serum vimentin levels are associated with the presence and the severity of CAD. Vimentin protein promotes atherogenesis in ApoE -/- mice., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Increased transcytosis of low-density lipoprotein (LDL) across the endothelium and oxidation of LDL deposited within the subendothelial space are crucial early events in atherogenesis. C1q/TNF-related protein (CTRP) 5 is a novel secreted glycoprotein and its biological functions are largely undefined., Methods: Expression of CTRP5 was analyzed in sera and atherosclerotic plaques of patients with coronary artery disease (CAD). The role of CTRP5 in atherogenesis was investigated in vitro and in vivo., Results: We found CTRP5 serum levels were higher in patients with than without CAD (247.26 ± 61.71 vs. 167.81 ± 68.08 ng/mL, p < 0.001), and were positively correlated with the number of diseased vessels (Spearman's r = 0.611, p < 0.001). Increased expression of CTRP5 was detected in human coronary endarterectomy specimens as compared to non-atherosclerotic arteries. Immunofluorescence further showed that CTRP5 was predominantly localized in the endothelium, infiltrated macrophages and smooth muscle cells in the neointima. In vivo and in vitro experiments demonstrated that CTRP5 promoted transcytosis of LDL across endothelial monolayers, as well as the oxidative modification of LDL in endothelial cells. Mechanistically, we found that CTRP5 up-regulated 12/15-lipoxygenase (LOX), a key enzyme in mediating LDL trafficking and oxidation, through STAT6 signaling. Genetic or pharmacological inhibition of 12/15-LOX dramatically attenuated the deposition of oxidized LDL in the subendothelial space and the development of atherosclerosis., Conclusions: These data indicate that CTRP5 is a novel pro-atherogenic cytokine and promotes transcytosis and oxidation of LDL in endothelial cells via up-regulation of 12/15-LOX., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Nonenzymatic glycation of apolipoproteins plays a role in the pathogenesis of the vascular complications of diabetes., Objectives: This study investigated whether apolipoprotein (apo) A-IV was glycated in patients with type 2 diabetes mellitus (T2DM) and whether apoA-IV glycation was related to coronary artery disease (CAD). The study also determined the biological effects of glycated apoA-IV., Methods: The authors consecutively enrolled 204 patients with T2DM without CAD (Group I), 515 patients with T2DM with CAD (Group II), and 176 healthy subjects (control group) in this study. ApoA-IV was precipitated from ultracentrifugally isolated high-density lipoprotein, and its glycation level was determined based on Western blotting densitometry (relative intensity of apoA-IV glycation). ApoA-IV NƐ-(carboxylmethyl) lysine (CML) modification sites were identified by mass spectrometry in 37 control subjects, 63 patients in Group I, and 138 patients in Group II. Saline or glycated apoA-IV (g-apoA-IV) generated by glyoxal culture was injected into apoE -/- mice to evaluate atherogenesis, and was also used for the cell experiments., Results: The relative intensity and the abundance of apoA-IV glycation were associated with the presence and severity of CAD in patients with T2DM (all p < 0.05). The experiments showed that g-apoA-IV induced proinflammatory reactions in vitro and promoted atherogenesis in apoE -/- mice through the nuclear receptor NR4A3. G-apoA-IV with mutations (K-A) at high-frequency glycation sites exhibited more weakened proinflammatory and atherogenic effects than did g-apoA-IV both in vitro and in vivo., Conclusions: ApoA-IV glycation is associated with CAD severity in patients with T2DM, and g-apoA-IV induces atherogenesis through NR4A3 in apoE -/- mice., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Macrophage is a major contributor to the development of atherosclerosis by taking up deposited lipoprotein and eliciting local inflammation. Previously, we and others have shown C1q/TNF-related proteins (CTRPs) play diverse roles in vascular functions. In this study, we sought to investigate the changes in CTRP expression levels during vital biological processes in macrophages and their relation to inflammatory responses., Methods: Western blot and real-time PCR were performed to analyze CTRPs expression levels in human peripheral blood mononuclear cells, primary macrophages and lipid-laden foam cells. Mechanisms that regulate CTPR1 expression were further investigated by bioinformatic analysis and chromatin immunoprecipitation. Enzyme-linked immunosorbent assay was performed to measure the concentration of inflammatory cytokines., Results: We found that almost all CTRPs were significantly increased in primary human macrophages after differentiation from peripheral blood mononuclear cells. In particular, CTRP1 was further up-regulated upon exposure to oxidized low-density lipoprotein (oxLDL) in a peroxisome proliferator-activated receptor (PPAR)-dependent manner. Chromatin immunoprecipitation also confirmed the presence of PPAR-γ in the CTRP1 promoter after oxLDL treatment. Stimulation of CTRP1 led to markedly enhanced secretion of pro-atherogenic factors, including MCP-1, TNF-α, IL-1β, and IL-6, whereas oxLDL-induced inflammatory cytokine production was significantly attenuated after the treatment with CTRP1 neutralizing antibody., Conclusions: These data suggest an essential role of CTRP1 in linking dysregulation of lipid metabolism and inflammatory responses in macrophages., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Aims: We investigated the association of the adipokine C1q/TNF-related protein (CTRP) 1 with coronary artery disease (CAD), and the biological vascular effects of CTRP1., Methods and Results: We analysed CTRP1 levels in sera of CAD patients (n = 451) and non-CAD controls (n = 686), and in coronary endarterectomy specimens (n = 32), non-atherosclerotic internal mammary arteries (n = 26), aortic atherosclerotic plaques (n = 15), and non-atherosclerotic aortic samples (n = 10). C1q/TNF-related protein-levels were higher in sera, endarterectomy specimens, aortic atherosclerotic plaques, and peripheral blood mononuclear cells (PBMCs) from CAD patients compared with controls, and were related to CAD severity. The production of CTRP1 was profusely induced by inflammatory cytokines and itself caused a concentration-dependent expression of adhesion molecules and inflammatory markers in human endothelial cells, human peripheral blood monocytes, and THP-1 cells. C1q/TNF-related protein-1 induced p38-dependent monocyte-endothelium adhesion in vitro and the recruitment of leucocytes to mesenteric venules in C57BL/6 mice. Immunohistochemistry of atherosclerotic femoral arteries exhibited CD68 and VE-cadherin loci-associated increased CTRP1 expression in plaques. Compared with saline, intraperitoneal injection of recombinant CTRP1 protein (200 μg/kg) every other day promoted atherogenesis in apoE(-/-) mice at 24 weeks. However, pro-atherogenic effects were significantly attenuated in CTRP1(-/-)/apoE(-/-) double-knockout mice compared with apoE(-/-) mice, with a consistent decrease in vascular adhesion molecule, phospho-p38 and TNF-α expression and macrophage infiltration in plaque in CTRP1(-/-) and double-knockout mice. Tumour necrosis factor-α-induced expression of adhesion molecules and cytokines were lower in primary endothelial cells and macrophages from CTRP(-/-) mice than in those from C57BL/6 mice., Conclusion: C1q/TNF-related protein-1 is a marker of atherosclerosis in humans and promotes atherogenesis in mice., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Objective: Early detection of atherosclerotic renal artery stenosis (ARAS) is clinically important with respect to blood pressure control, prevention of renal insufficiency, and even improving survival. We investigated whether the presence of significant ARAS (luminal diameter narrowing ≥70%) could be predicted using a logistic regression model before coronary angiography/intervention., Methods: Initially, we developed a logistic regression model for detecting significant ARAS based upon clinical and angiographic features and biochemical measurements in a cohort of 1813 patients undergoing transfemoral coronary and renal angiography. This model was then prospectively applied to an additional 495 patients who received transradial renal angiography to ascertain its predictive accuracy for the presence of significant ARAS., Results: Multivariate regression analysis revealed that older age (≥65 years), resistant hypertension, type 2 diabetes, creatinine clearance (Ccr) ≤60 ml/min, and multivessel coronary disease were independent predictors for significant ARAS. A logistic regression model for detecting ARAS by incorporating conventional risk factors and multivessel coronary disease was generated as: P/(1-P)=exp(-2.618+1.112[age≥65 years]+1.891[resistant hypertension]+0.453[type 2 diabetes]+0.587[Ccr≤60 ml/min]+2.254[multivessel coronary disease]). When this regression model was prospectively applied to the additional 495 patients undergoing transradial coronary and renal angiography, significant ARAS could be detected with a sensitivity of 81.2%, specificity of 88.9%, and positive and negative predictive accuracies of 53.8% and 96.7%, respectively., Conclusions: The logistic regression model generated in this study may be useful for screening for significant ARAS in patients undergoing transradial coronary angiography/intervention.

Objective: This study evaluated the relationship between serum levels of endogenous secretory receptor for advanced glycation endproducts (esRAGE) and coronary plaque progression in diabetic and nondiabetic patients., Design and Methods: Serum esRAGE level was measured and quantitative coronary angiography (QCA) was performed in 265 consecutive patients at baseline and 1-year follow-up., Results: Comparing to baseline, serum esRAGE level was significantly increased during follow-up in nondiabetic patients without plaque progression (p=0.014), unchanged in nondiabetic patients with plaque progression and diabetic patients without plaque progression, and decreased in diabetic patients with plaque progression (p=0.011). Moreover, change of esRAGE levels correlated with change of QCA measurements. Multivariable regression analyses revealed that high-density lipoprotein cholesterol (OR=0.214, p=0.037), hypertension (OR=2.755, p=0.011), high-sensitivity C-reactive protein (OR=1.083, p<0.001) and change of esRAGE (OR=23.477, p<0.001) were independent risk factors for plaque progression in diabetic patients., Conclusions: This study demonstrated an association of decreased serum esRAGE level with coronary plaque progression in patients with diabetes.

Background: Chronic inflammatory disorders and dyslipidemia in type 2 diabetes mellitus (T2DM) are essential contributors to the development of atherosclerotic cardiovascular disease. Monocyte to high-density lipoprotein cholesterol (HDL-C) ratio (MHR) is a novel and simple measure associated positively with the body inflammatory and oxidative stress status. However, little is known regarding the role of MHR in evaluating carotid intima-media thickness (CIMT), a surrogate predictor of subsequent vascular events, especially in diabetic patients. Methods: A total of 494 patients with T2DM and 1,848 non-diabetic subjects were consecutively enrolled in study 1. Correlation between MHR and CIMT was compared between diabetic and non-diabetic subjects. In study 2, a total of 110 T2DM patients from study 1 with normal basal CIMT and a follow-up ultrasonography at 12 months were enrolled. The predictive role of MHR on CIMT progression in diabetic patients was analyzed. Results: In study 1, MHR was higher in patients with T2DM than non-diabetic subjects (p < 0.001). After adjustment for confounding risk factors, MHR remained correlated significantly with CIMT in diabetic (r = 0.172, p = 0.001) but not non-diabetic (r = 0.006, p = 0.813) subjects. Logistic regression analyses demonstrated that MHR is superior to traditional lipid parameters in association with elevated CIMT in diabetic patients. In study 2, MHR at baseline was positively correlated with change in CIMT (r = 0.313, p = 0.001). Basal MHR was independently associated with change in CIMT [β = 0.059, (95% CI: 0.012–0.105), p = 0.014] in multivariate linear regression analysis. Conclusions: Our study suggests that MHR is a convenient and effective measure in prediction of the presence and progression of subclinical carotid atherosclerosis in patients with T2DM. [ABSTRACT FROM AUTHOR]

Oxidized low-density lipoprotein (oxLDL)-regulated secretion of inflammatory cytokines in smooth muscle cells (SMCs) is regarded as an important step in the progression of atherosclerosis; however, its underlying mechanism remains unclear. This study investigated the role of toll-like receptor 4 (TLR4) in oxLDL-induced expression of inflammatory cytokines in SMCs both in vivo and in vitro. We found that the levels of TLR4, interleukin 1-β (IL1-β), tumor necrosis factor-α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and matrix metalloproteinase-2 (MMP-2) expression were increased in the SMCs of atherosclerotic plaques in patients with femoral artery stenosis. In cultured primary arterial SMCs from wild type mice, oxLDL caused dose- and time-dependent increase in the expression levels of TLR4 and cytokines. These effects were significantly weakened in arterial SMCs derived from TLR4 knockout mice (TLR4−/−). Moreover, the secretion of inflammatory cytokines was blocked by TLR4-specific antibodies in primary SMCs. Ox-LDL induced activation of p38 and NFκB was also inhibited in TLR4−/− primary SMCs or when treated with TLR4-specific antibodies. These results demonstrated that TLR4 is a crucial mediator in oxLDL-induced inflammatory cytokine expression and secretion, and p38 and NFκB activation. [ABSTRACT FROM AUTHOR]

Abstract: Atherosclerosis is an inflammatory process due to oxidized low-density lipoprotein (oxLDL) accumulation in macrophages. We investigated the involvement of microRNAs in oxLDL accumulation and inflammatory response in macrophages. The expression of miR-146a decreases under oxLDL stimulation. MiR-146a significantly reduces intracellular LDL cholesterol content and secretion of interleukin 6, interleukin 8, chemokine (C–C motif) ligand 2 and matrix metallopeptidase 9. Toll-like receptor 4 (TLR4) is a relevant target of miR-146a, and miR-146a inhibits the activation of TLR4-dependent intracellular signaling pathways involved in cytoskeleton rearrangement, lipid uptake, and inflammatory cytokine secretion. These results indicate that miR-146a contributes to the regulation of both oxLDL accumulation and inflammatory response by negatively regulating TLR4 and thereby inhibiting the activation of TLR4-dependent signaling pathways. Over-expression of miR-146a may be useful in the prevention and treatment of atherosclerosis. [Copyright &y& Elsevier]

Background: The extent of coronary collateral formation is a primary determinant of the severity of myocardial damage and mortality after coronary artery occlusion. Type 2 diabetes mellitus (T2DM) represents an important risk factor for impaired collateral vessel growth. However, the mechanism of reduced coronary collateralization in type 2 diabetic patients remains unclear. Methods: With the reference to the recent researches, this review article describes the pathogenic effects of T2DM on collateral development and outlines possible clinical and biochemical markers associated with reduced coronary collateralization in type 2 diabetic patients with chronic total occlusion (CTO). Results: Diffuse coronary atherosclerosis in T2DM reduces pressure gradient between collateral donor artery and collateral recipient one, limiting collateral vessel growth and function. An interaction between advanced glycation end-products and their receptor activates several intracellular signaling pathways, enhances oxidative stress and aggravates inflammatory process. Diabetic condition decreases pro-angiogenic factors especially vascular endothelial growth factor and other collateral vessel growth related parameters. Numerous clinical and biochemical factors that could possibly attenuate the development of coronary collaterals have been reported. Increased serum levels of glycated albumin, cystatin C, and adipokine C1q tumor necrosis factor related protein 1 were associated with poor coronary collateralization in type 2 diabetic patients with stable coronary artery disease and CTO. Diastolic blood pressure and stenosis severity of the predominant collateral donor artery also play a role in coronary collateral formation. Conclusions: T2DM impairs collateral vessel growth through multiple mechanisms involving arteriogenesis and angiogenesis, and coronary collateral formation in patients with T2DM and CTO is influenced by various clinical, biochemical and angiographic factors. This information provides insights into the understanding of coronary pathophysiology and searching for potential new therapeutic targets in T2DM. [ABSTRACT FROM AUTHOR]