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In vivo and in vitro studies have demonstrated that thrombospondin-1 (TSP-1) is involved in atherosclerotic pathogenesis. However, the role of TSP-1 in clinical atherosclerosis remains unknown. This cross-sectional study investigated the relationship between TSP-1 and carotid intima-media thickness (IMT) and examined whether it interacts with conventional cardiovascular risk factors. A total of 587 participants were enrolled from February 2018 to December 2021. TSP-1 was dichotomized based on median value. Carotid IMT was measured bilaterally in each segment, and the average value was taken as the overall IMT variable. Analysis of covariance models were used to ascertain the main and interaction effects of cardiovascular risk factors and circulating TSP-1 levels on carotid IMT. Those with high TSP-1 (n = 294) had significantly higher carotid IMT than did those with low TSP-1 (n = 293; 0.74 ± 0.12 vs 0.72 ± 0.11 mm; p = 0.011). After the combined effects of TSP-1 and vascular risk factors on carotid IMT were evaluated, an interaction effect on IMT was observed between TSP-1 and hypertension (adjusted F = 8.760; p = 0.003). Stratification analysis revealed that individuals with hypertension and high TSP-1 had significantly higher IMT than did those with low TSP-1 (adjusted p = 0.007). However, this difference was not observed in normotensive individuals (adjusted p = 0.636). In conclusion, this is the first study to provide clinical data supporting the correlation between TSP-1 and atherosclerosis. TSP-1 may be a crucial marker of increased susceptibility to atherosclerosis in individuals with hypertension., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

MicroRNAs are endogenously expressed small noncoding RNAs that regulate gene expression at the post-transcriptional level. MicroRNAs have emerged as key regulators of several physiological and pathophysiological processes in the cardiovascular system. Aberrant expression of microRNAs has been implicated in the pathophysiological processes underlying the development of atherosclerosis and cardiovascular disease, including change in endothelial function, vascular smooth muscle cell proliferation and migration, macrophage function, and foam cell formation. In this review, we summarize the recent data showing the roles of microRNAs in cell studies, studies on atherosclerotic mice, and human studies., (Copyright © 2012. Published by Elsevier B.V.)

Aim of the Study: San-huang-xie-xin-tang (SHXXT) is a traditional Chinese medicine and it has been shown to have an anti-inflammatory effect. Since inflammation is one of the major mechanisms of atherosclerosis, we aimed to investigate anti-atherosclerotic effect of SHXXT in human aortic smooth muscle cells (HASMCs)., Materials and Methods: Human aortic smooth muscle cells (HASMCs) were used in the present study, and rendered atherosclerosis by adding lipopolysaccharides. We first tested the effects of SHXXT on HASMC migration and proliferation as they present the major morphological change of atherosclerosis. We also examined whether SHXXT can influence the production of several biomarkers of inflammation and atherosclerosis including reactive oxygen species (ROS), COX-2, ERK1/2, IL-1β, IL-6, IL-8 and MCP-1., Results: Using the dimethyl-thiazol-diphenyltetrazoliumbromide (MTT) and wound repair assay, SHXXT was shown to significantly reduce HASMC proliferation and migration, respectively. From the fluorometric assay, SHXXT significantly reduced ROS production. SHXXT down regulated mRNA and protein levels for the COX-2 gene. In addition, phosphorylated ERK1/2 levels were suppressed by SHXXT suggesting HASMC division can be inhibited under pro-inflammatory condition. SHXXT significantly inhibited the production of IL-1β, IL-6, IL-8 and MCP-1 after LPS stimulation., Conclusions: Our results indicated that SHXXT can influence several mechanisms involved in atherosclerosis, which suggests that SHXXT may have a therapeutic potential for cardiovascular disease associated with atherosclerosis., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: We assessed the correlation between intima-media thickness (IMT) and stiffness and test whether they are independent risk factors for atherosclerotic diseases., Methods: We enrolled 2333 participants from the general population. Among the study subjects, 197 subjects had a history of stroke or myocardial infarction (MI) and were treated as patients, and the rest were the control subjects. Intima-media thickness was measured at the common carotid artery (CCA), bifurcation, and internal carotid artery. Three parameters (arterial stiffness [beta], elastic modulus, and pulse wave velocity) were measured for carotid stiffness. Correlation between IMT and stiffness was first calculated. Multivariate regression model was used to evaluate whether inclusion of both IMT and stiffness can increase the prediction of cardiovascular events., Results: Only CCA and bifurcation IMTs were significantly and positively correlated with stiffness. After adjusting for age and sex, the correlations were substantially attenuated. Common carotid artery IMT was most significantly associated with stroke and MI (P = 2.6 x 10) followed by bifurcation IMT (P = 5.5 x 10), and internal carotid artery IMT was least significant (P = 0.02). For stiffness, beta was most significant (P = 3.6 x 10) for stroke and MI, followed by elastic modulus (P = 1.1 x 10) and pulse wave velocity (P = 6.8 x 10). The best model for the combined effect was from beta (P < 0.03) and CCA (P = 0.056) or bifurcation IMT (P = 0.057)., Conclusions: Carotid IMT and stiffness represent different properties of atherosclerotic vessel wall. Measuring both traits provides a better characterization of atherosclerosis.

Background: Brachial artery flow-mediated dilation (FMD) is a non-invasive measure of endothelial function. Endothelial dysfunction has been associated with traditional vascular risk factors and increased risk of cardiovascular disease. The importance of genetic contribution to FMD and baseline brachial artery diameter has not been shown in Hispanic populations. The purpose of this study was to estimate the heritability of FMD., Methods: Flow mediated dilation and brachial artery diameter were measured in a subset of Caribbean Hispanic families from the ongoing Northern Manhattan Family Study (NOMAFS), which studies the contribution of genetics to stroke and cardiovascular risk factors. The age- and sex-adjusted heritability of FMD was estimated using variance component methods., Results: The current data include 620 subjects (97 probands and 523 relatives) from 97 families. The age and sex-adjusted heritability of brachial artery diameter was 0.57 (p<0.01). The age- and sex-adjusted heritability of FMD was 0.20 (p=0.01). After additional adjustment for systolic and diastolic blood pressure, body mass index, smoking, lipid, diabetes mellitus, medication, and baseline brachial artery diameter, the heritability of FMD was 0.17 (p=0.01)., Conclusions: We found modest heritability of FMD. FMD might be a reasonable phenotype for further investigation of genetic contribution to atherosclerosis.

Background/Aims: MicroRNA miR-21, miR-221 and miR-145 have been implicated in the cardiovascular system. We aimed to compare the serum levels of the three microRNAs (miRNAs) in different severities of cerebrovascular diseases and evaluate the feasibility of using these miRNAs as biomarkers for stroke. Methods: We enrolled 167 subjects with ischemic stroke, 66 atherosclerosis subjects with any carotid plaque score and 157 healthy controls. These three types of subjects represent three levels of severity in cerebrovascular diseases. Analysis of covariance was used to evaluate the relationship between miRNAs and disease severity with adjustment for conventional risk factors. To test the prediction for stroke, we built regression models containing the serum miRNA levels and risk factors. Prediction capabilities were compared by the receiver operating characteristic curves. Results: Stroke patients and atherosclerosis subjects had significantly higher miR-21 and lower miR-221 serum levels than healthy controls, while the miR-145 expression was too low to provide useful information in this regard. The best model showed that miR-21 and miR-221 were independent predictors. There was a 6.2-fold increase for stroke risk when miR-21 levels increase by log102-ΔCt = 1, while a 10.4-fold increase was observed as miR-221 decreases by log102-ΔCt = 1. Conclusions: Serum miR-145 was not detected in over 50% of the patients and it may not be an ideal marker to predict stroke. MiR-21 and miR-221 are novel biomarkers for atherosclerosis and stroke. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims Proliferation and migration of vascular smooth muscle cells (VSMCs) can cause atherosclerosis and neointimal formation. MicroRNAs have been shown to regulate cell proliferation and phenotype transformation. We discovered abundant expression of microRNA-195 in VSMCs and conducted a series of studies to identify its function in the cardiovascular system. Methods and results MicroRNA-195 expression was initially found to be altered when VSMCs were treated with oxidized low-density lipoprotein (oxLDL) in a non-replicated microRNA array experiment. Using cellular studies, we found that microRNA-195 reduced VSMC proliferation, migration, and synthesis of IL-1β, IL-6, and IL-8. Using bioinformatics prediction and experimental studies, we showed that microRNA-195 could repress the expression of Cdc42, CCND1, and FGF1 genes. Using a rat model, we found that the microRNA-195 gene, introduced by adenovirus, substantially reduced neointimal formation in a balloon-injured carotid artery. In situ hybridization confirmed the presence of microRNA-195 in the treated arteries but not in control arteries. Immunohistochemistry experiments showed abundant Cdc42 in the neointima of treated arteries. Conclusions We showed that microRNA-195 plays a role in the cardiovascular system by inhibiting VSMC proliferation, migration, and proinflammatory biomarkers. MicroRNA-195 may have the potential to reduce neointimal formation in patients receiving stenting or angioplasty. [ABSTRACT FROM AUTHOR]

Objectives: Coronary artery disease (CAD) is a multifactorial disease and influenced by genetics. We previously reported that a single nucleotide polymorphism (rs11066001) in the BRAP gene was related to the risk of myocardial infarction. However, it is unclear whether rs11066001 is associated with the extent of coronary atherosclerosis. Methods: We enrolled 732 patients scheduled for diagnostic coronary angiography. Angiographic presence of significant CAD (0 or 1), clinical vessel score (CVS, 0-3 vessels) and diffuse score (DS, 0-11.5) were used to evaluate the extent of coronary atherosclerosis. Genotyping was carried out by the TaqMan technology. Results: Of all patients, 558 (76.2%) had significant CAD. The odds ratio for the GG to the AA genotype was 2.45 (95% CI 1.13-5.34, p = 0.024) for the presence of significant CAD. The CVS was correlated with the frequency of genotypes in the recessive model (p = 0.001). Regression analysis showed a significant association between rs11066001 and the presence of significant CAD and DS (all p < 0.05). There was a synergistic effect between rs11066001 and diabetes on the occurrence of significant CAD (p < 0.001 for interaction). Conclusion: The BRAP rs11066001 gene is associated with the extent of coronary atherosclerosis and has a synergistic effect with diabetes on the occurrence of significant CAD in the Chinese population. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Connexin 37, encoded by the GJA4 gene, protects against atherosclerosis. A recent study reported an association between polymorphism rs1764391 at GJA4 and ischemic stroke in a Chinese population. We aimed to replicate this result. Materials and Methods: A total of 958 ischemic stroke patients and 2196 controls were enrolled for the study. All participants were Chinese residing in Taiwan. Logistic regression analysis with adjustment for traditional risk factors was used to estimate the genetic effect. We also performed stratification analyses by sex and stroke subtypes. Literature reviews were conducted for available genetic association studies investigating rs1764391 and cardiovascular phenotypes. Results: We did not find any significant association for overall stroke (p=0.87) or from any subset analyses. Eight studies addressing the associations between rs1764391 and cardiovascular phenotypes had a sample size greater than 1000. Including the present study, five out of the eight large-scale studies found no association. Conclusions: GJA4 polymorphism is not associated with stroke risk in the Taiwanese population. [Copyright &y& Elsevier]

Background and purpose Parental stroke is a risk factor for stroke among the offspring. Carotid artery intima-media thickness (IMT) is a widely regarded surrogate marker for atherosclerosis and a predictive marker for stroke. This study examines whether parental stroke is associated with IMT progression. Methods This longitudinal study had two measures of IMT that were taken upon enrollment of the 521 subjects and after an average follow-up of 4.1 years. The rate of IMT progression was tested for associations with parental stroke and cardiovascular risk factors using ANCOVA models. Age and sex were also tested as effect modifiers. The subjects were allocated into the young or old group using the age of 55 years. Results Parental history of stroke was significantly associated with progression of common carotid artery (CCA) IMT compared with no parental stroke history (13.52 vs. 10.43 μm/year, adjusted p = 0.035). The parental effect on IMT progression of the bifurcation and internal carotid artery was dependent on age group. Young subjects had faster progression, whereas older subjects with parental stroke had slower progression. There was a three-way interaction among sex, age, and parental stroke in CCA IMT progression, such that young women with parental stroke had a 69.7% faster progression than young women without parental stroke (15.58 vs. 9.18 μm/year). However, this difference was not found in young men or old subjects with and without parental stroke. Conclusions Parental stroke is associated with carotid artery IMT progression and is more obvious in the young, especially among women. The results emphasize the clinical significance of parental stroke risk on atherosclerosis in young women. [ABSTRACT FROM AUTHOR]

Abstract: MicroRNA-29b has been reported to epigenetically regulate proatherogenic genes in response to oxLDL. Since transcription factors and epigenetic regulations are important mechanisms to regulate gene expression, we investigated whether these mechanisms are involved in oxLDL-induced microRNA-29b upregulation. First, we confirmed that microRNA-29b expression was increased in the aorta of mice fed with a high-fat diet, which was consistent with our previous in vitro findings. Next, we found that oxLDL only activated the microRNA-29b-1/microRNA-29a cluster gene on chromosome 7 but not the other distinct microRNA-29b gene located on chromosome 1. Using the promoter reporter assay and chromatin immunoprecipitation, activator protein-1 (AP-1) was shown to bind to the microRNA-29b-1 promoter. We further identified the signaling pathway of LOX-1/Ca2+/ROS/ERK/c-Fos was involved in oxLDL-mediated microRNA-29b overexpression after treating with the MAPTAM (Ca2+ chelator), NAC (ROS scavenger), U0126 (ERK inhibitor) and c-Fos (one of the AP-1 proteins) shRNA, respectively. To investigate epigenetic regulations, we found that microRNA-29b promoter contained no CpG islands for DNA methylation. Therefore we investigated whether histone modifications influence microRNA-29b promoter activity. We showed that down-regulation of HDAC1 and the modifications on histone 3 lysine 4 (H3K4) and H3K9 significantly affected microRNA-29b expression. Furthermore, knockdown of c-Fos expression attenuated the effect of oxLDL-induced histone modifications on the microRNA-29b gene expression. Taken together, our data suggest that both transcription factor activation and histone modifications are important regulatory mechanisms of oxLDL-induced atherogenic process. This article is part of a Special Issue entitled OxLDL causes both epigenetic modification and signaling regulation on the microRNA-29b gene: Novel mechanisms for cardiovascular diseases. [Copyright &y& Elsevier]