Ming-Jie Zhang

An overview of potential molecular mechanisms involved in VSMC phenotypic modulation

The fully differentiated medial vascular smooth muscle cells (VSMCs) of mature vessels keep quiescent and contractile. However, VSMC can exhibit the plasticity in phenotype switching from a differentiated and contractile phenotype to a dedifferentiated state in response to alterations in local environmental cues, which is called phenotypic modulation or switching. Distinguishing from its differentiated state expressing more smooth muscle (SM)-specific/selective proteins, the phenotypic modulation in VSMC is characterized by an increased rate of proliferation, migration, synthesis of extracellular matrix proteins and decreased expression of SM contractile proteins. Although it has been well demonstrated that phenotypic modulation of VSMC contributes to the occurrence and progression of many proliferative vascular diseases, little is known about the details of the molecular mechanisms of VSMC phenotypic modulation. Growing evidence suggests that variety of molecules including microRNAs, cytokines and biochemical factors, membrane receptors, ion channels, cytoskeleton and extracellular matrix play important roles in controlling VSMC phenotype. The focus of the present review is to provide an overview of potential molecular mechanisms involved in VSMC phenotypic modulation in recent years. To clarify VSMC differentiation and phenotypic modulation mechanisms will contribute to producing cell-based therapeutic interventions for aberrant VSMC differentiation-related diseases.

Influence of ATP-binding cassette transporter 1 R219K and M883I polymorphisms on development of atherosclerosis: a meta-analysis of 58 studies.

Background Numerous epidemiological studies have evaluated the associations between ATP-binding cassette transporter 1 (ABCA1) R219K (rs2230806) and M883I (rs4149313) polymorphisms and atherosclerosis (AS), but results remain controversial. The purpose of the present study is to investigate whether these two polymorphisms facilitate the susceptibility to AS using a meta-analysis. Methods PubMed, Embase, Web of Science, Medline, Cochrane database, Clinicaltrials.gov, Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI, Google Scholar and Baidu Library were searched to get the genetic association studies. All statistical analyses were done with Stata 11.0. Results Forty-seven articles involving 58 studies were included in the final meta-analysis. For the ABCA1 R219K polymorphism, 42 studies involving 12,551 AS cases and 19,548 controls were combined showing significant association between this variant and AS risk (for K allele vs. R allele: OR = 0.77, 95% CI = 0.71–0.84, P<0.01; for K/K vs. R/R: OR = 0.60, 95% CI = 0.51–0.71, P<0.01; for K/K vs. R/K+R/R: OR = 0.69, 95% CI = 0.60–0.80, P<0.01; for K/K+R/K vs. R/R: OR = 0.74, 95% CI = 0.66–0.83, P<0.01). For the ABCA1 M883I polymorphism, 16 studies involving 4,224 AS cases and 3,462 controls were combined. There was also significant association between the variant and AS risk (for I allele vs. M allele: OR = 0.85, 95% CI = 0.77–0.95, P<0.01). Conclusions The present meta-analysis suggested that the ABCA1 R219K and M883I polymorphisms were associated with the susceptibility to AS. However, due to the high heterogeneity in the meta-analysis, the results should be interpreted with caution.

Influence of interleukin-6 gene -174G>C polymorphism on development of atherosclerosis: a meta-analysis of 50 studies involving 33,514 subjects.

Increasing epidemiological studies have focused on the associations between interleukin-6 (IL-6) gene -174G>C polymorphism and atherosclerotic diseases, but the results are still controversial. This meta-analysis was designed to identify whether this association exists. PubMed, Embase, Web of Science, Cochrane database, Clinicaltrials.gov and Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI and Google Scholar were searched to get the genetic association studies. The crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the IL-6 gene -174G>C polymorphism and atherosclerosis ( AS ) risk. The subgroup analyses were made on the following: ethnicity, atherosclerotic diseases and source of controls. Finally, 50 studies (15,029 cases and 18,485 controls) were included in this meta-analysis. Overall, no significant association was found between the IL-6 gene -174G>C polymorphism and AS risk (for C allele vs. G allele: OR=1.02, 95% CI=0.94-1.11, p=0.64; for C/C vs. G/G: OR=1.01, 95% CI=0.85-1.21, p=0.88; for C/C vs. C/G+G/G: OR=0.97, 95% CI=0.84-1.12, p=0.68; for C/C+C/G vs. G/G: OR=1.07, 95% CI=0.97-1.17, p=0.18). In the subgroup analyses, significant associations were found between the IL-6 gene -174G>C polymorphism and AS in non-Caucasian group (for CC+CG vs. GG: OR=1.22, 95% CI=1.06-1.41, p=0.005), other atherosclerotic diseases group (for C allele vs. G allele: OR =0.75, 95% CI=0.61-0.93, p=0.008; for C/C vs. G/G: OR=0.56, 95% CI=0.38-0.81, p=0.002; for C/C vs. C/G+G/G: OR=0.60, 95% CI=0.45-0.79, p=0.0004) and population-based group (for C allele vs. G allele: OR=1.09, 95% CI=1.00-1.18, p=0.04; for CC+CG vs. GG: OR=1.15, 95% CI=1.04-1.27, p=0.005). In summary, the present meta-analysis suggests that the IL-6 gene -174G C polymorphism is associated with the susceptibility to AS. However, due to the high heterogeneity in the meta-analysis, the results should be interpreted with caution.

PPARγ Inhibits VSMC Proliferation and Migration via Attenuating Oxidative Stress through Upregulating UCP2

Increasing evidence showed that abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are common event in the pathophysiology of many vascular diseases, including atherosclerosis and restenosis after angioplasty. Among the underlying mechanisms, oxidative stress is one of the principal contributors to the proliferation and migration of VSMCs. Oxidative stress occurs as a result of persistent production of reactive oxygen species (ROS). Recently, the protective effects of peroxisome proliferator-activated receptor γ (PPARγ) against oxidative stress/ROS in other cell types provide new insights to inhibit the suggests that PPARγ may regulate VSMCs function. However, it remains unclear whether activation of PPARγ can attenuate oxidative stress and further inhibit VSMC proliferation and migration. In this study, we therefore investigated the effect of PPARγ on inhibiting VSMC oxidative stress and the capability of proliferation and migration, and the potential role of mitochondrial uncoupling protein 2 (UCP2) in oxidative stress. It was found that platelet derived growth factor-BB (PDGF-BB) induced VSMC proliferation and migration as well as ROS production; PPARγ inhibited PDGF-BB-induced VSMC proliferation, migration and oxidative stress; PPARγ activation upregulated UCP2 expression in VSMCs; PPARγ inhibited PDGF-BB-induced ROS in VSMCs by upregulating UCP2 expression; PPARγ ameliorated injury-induced oxidative stress and intimal hyperplasia (IH) in UCP2-dependent manner. In conclusion, our study provides evidence that activation of PPARγ can attenuate ROS and VSMC proliferation and migration by upregulating UCP2 expression, and thus inhibit IH following carotid injury. These findings suggest PPARγ may represent a prospective target for the prevention and treatment of IH-associated vascular diseases.

The role of TRPV1 in improving VSMC function and attenuating hypertension

The transient receptor potential vanilloid type 1 (TRPV1) channel, a ligand-gated cation channel of the TRP subfamily, can be activated by multiple stimuli, including capsaicin. Currently, cumulative studies have demonstrated an interesting link between TRPV1 and cardiovascular diseases, including hypertension. Additionally, the protective effect of TRPV1 against hypertension and its related disorders has been proved to be partly involved with the improved action of vascular smooth muscle cells (VSMCs). This review focuses on the current knowledge of TRPV1 in improving VSMC function and attenuating hypertension.

SIRT1 improves VSMC functions in atherosclerosis

Despite advancements in diagnosis and treatment of cardiovascular diseases (CVDs), the morbidity and mortality of CVDs are still rising. Atherosclerosis is a chronic inflammatory disease contributing to multiple CVDs. Considering the complexity and severity of atherosclerosis, it is apparent that exploring the mechanisms of atherosclerotic formation and seeking new therapies for patients with atherosclerosis are required to overcome the heavy burden of CVDs on the quality and length of life of the global population. Vascular smooth muscle cells (VSMCs) play a dominant role in functional and structural changes of the arterial walls in response to atherogenic factors. Therefore, improvement of VSMC functions will slow down the development of atherosclerosis to a large extent. Given its protective performances on regulation of cholesterol metabolism and inflammatory responses, SIRT1 has long been known as an anti-atherosclerosis factor. In this review, we focus on the effects of SIRT1 on VSMC functions and thereby the development of atherosclerosis.

A meta-analysis of the relationship between MTHFR gene A1298C polymorphism and the risk of adult stroke.

Background: The association between methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism and adult stroke remains controversial. The present article was designed to clarify this relationship through pooled analysis of the numerous epidemiological studies focusing on this association. Methods: We comprehensively searched all published papers in electronic database including PubMed, Embase, Web of Science, Chinese Biomedical Literature on disc (CBMdisc) and China National Knowledge Infrastructure (CNKI) up to 2013. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) for allelic (C allele vs. A allele), additive (CC vs. AA), dominant (CC+AC vs. AA), and recessive (CC vs. AA+AC) models were calculated. Subgroup and sensitivity analyses were performed to detect the heterogeneity and examine the reliability of results, respectively. Beggs funnel plots and Eggers regression test were used to assess the potential publication bias. Results: A total of fifteen studies containing 2,361 cases and 2,653 controls were included in the final meta-analysis. The combined results of overall analysis showed that there was significant association between MTHFR gene A1298C polymorphism and adult stroke (allelic model: OR = 1.36, 95% CI = 1.11-1.67; additive model: OR = 1.88, 95% CI = 1.12-3.18; dominant model: OR = 1.33, 95% CI = 1.08-1.65 and recessive model: OR = 1.77, 95% CI = 1.07-2.94, respectively). On subgroup analysis by ethnicity of study population, significant association was shown in meta-analysis based on Asian population (allelic model: OR = 1.40, 95% CI = 1.19-1.65; additive model: OR = 2.58, 95% CI = 1.34-4.96; dominant model: OR = 1.44, 95% CI = 1.20-1.73 and recessive model: OR = 2.12, 95% CI = 1.20-3.76, respectively), but not in Caucasian population (allelic model: OR = 1.30, 95% CI = 0.93-1.82; additive model: OR = 1.65, 95% CI = 0.81-3.33; dominant model: OR = 1.17, 95% CI = 0.86-1.61 and recessive model: OR = 1.70, 95% CI = 0.83-3.50, respectively). In addition, the heterogeneity was effectively removed or decreased by limiting the included studies with population of Asian ethnicity. Furthermore, the corresponding pooled ORs were not materially changed in all genetic models of meta-analysis after limiting the included studies with population-based controls. However, except the recessive model, publication bias presented in the allelic, additive, dominant models identified by the Beggs funnel plots and Eggers regression test. Conclusions: In conclusion, the overall analysis suggests that MTHFR gene A1298C polymorphism plays an important role in the development of adult stroke. Genotype CC of MTHFR-1298A/C could increase the risk of stroke and may act as a predictor for clinical evaluation, especially in the Asian population. More studies with large-scale and different ethnicities are required to further confirm our findings. i 2014 S. Karger AG, Basel

TRPV1 attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation in hypertension

The phenotypic modulation of contractile vascular smooth muscle cell (VSMC) is widely accepted as the pivotal process in the arterial remodeling induced by hypertension. This study aimed to investigate the potential role of transient receptor potential vanilloid type 1 (TRPV1) on regulating VSMC plasticity and intracranial arteriole remodeling in hypertension. Spontaneously hypertensive rats (SHR), Wistar–Kyoto (WKY) rats and TRPV1−/− mice on a C57BL/6J background were used. By microscopic observation of the histopathological sections of vessels from hypertensive SHR and age-matched normotensive WKY control rats, we found that hypertension induced arterial remodeling. Decreased α-smooth muscle actin (α-SMA) and SM22α while increased osteopontin (OPN) were observed in aorta and VSMCs derived from SHR compared with those in WKY, and VSMCs derived from SHR upregulated inflammatory factors. TRPV1 activation by capsaicin significantly increased expression of α-SMA and SM22α, reduced expression of OPN, retarded proliferative and migratory capacities and inhibited inflammatory status in VSMCs from SHR, which was counteracted by TRPV1 antagonist 5′-iodoresiniferatoxin (iRTX) combined with capsaicin. TRPV1 activation by capsaicin ameliorated intracranial arteriole remodeling in SHR and deoxycorticosterone acetate (DOCA)-salt hypertensive mice. However, the attenuation of arteriole remodeling by capsaicin was not observed in TRPV1−/− mice. Furthermore, TRPV1 activation significantly decreased the activity of PI3K and phosphorylation level of Akt in SHR-derived VSMCs. Taken together, we provide evidence that TRPV1 activation by capsaicin attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation during hypertension, which may be at least partly attributed to the suppression PI3K/Akt signaling pathway. These findings highlight the prospect of TRPV1 in prevention and treatment of hypertension.

Association between intercellular adhesion molecule-1 gene K469E polymorphism and the risk of stroke in a Chinese population: a meta-analysis

Several epidemiologic studies have evaluated the association between intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism and stroke, but the results were inconsistent. The present meta-analysis was performed to investigate the relationship between K469E polymorphism and stroke in the Chinese population. A comprehensive search for related studies from the electronic databases of PubMed, Embase, Web of Science, CBMdisc and CNKI as well as a manual search of the references of identified articles was performed. Data were extracted to calculate for allelic, additive, dominant and recessive models using pooled odds ratios (ORs) along with 95% confidence intervals (CIs) by Review Manager 5.0 and Stata 11.0. Different effect models, subgroup analysis, sensitivity analysis, publication bias and power calculations were used to improve the comprehensive analysis. Finally, a total of 12 studies containing 1593 cases and 1555 controls were included in the final meta-analysis. No evidence of significant association between ICAM-1 gene K469E polymorphism and stroke was found in all four models (allelic model: OR = 1.07, 95%CI = 0.78–1.47; additive model: OR = 1.21, 95% CI = 0.67–2.16 (EE vs. KK); OR = 1.04, 95%CI = 0.75–1.45 (EK vs. KK); dominant model: OR = 1.07, 95% CI = 0.73–1.56; and recessive model: OR = 1.18, 95% CI = 0.77–1.83, respectively) based on the overall population, as well as subgroup analysis and sensitivity analysis. In conclusion, the present meta-analysis showed no evidence of significant association between ICAM-1 gene K469E polymorphism and stroke in the Chinese population. Nonetheless, this conclusion should be interpreted cautiously due to the low statistical power and considerable heterogeneity. Therefore, larger sample-size studies with homogeneous cases and well-matched controls are needed to further address this correlation.

Interleukin-18 gene promoter 607A polymorphism, but not 137C polymorphism, is a protective factor for ischemic stroke in the Chinese population: A meta-analysis.

Some epidemiological studies have evaluated the association between interleukin (IL)-18 promoter polymorphisms and the risk of ischemic stroke (IS), but the results were inconsistent. The present meta-analysis was therefore performed to investigate the relationship between IL-18 promoter 137G/C and 607C/A polymorphisms and the risk of IS in the Chinese population. Related studies from PubMed, Embase, Web of Science, CBMdisc and CNKI databases up to November 1, 2014 were systematically searched, also the reference lists of identified articles were manually searched. Information was extracted to calculate for the allelic, genotypic, dominant and recessive models using the pooled odds ratios (ORs) along with 95% confidence intervals (CIs). Evidence of significant association between 607C/A polymorphism and risk of IS was found in four genetic models based on the overall population. However, no significant association between 137G/C polymorphism and risk of IS was found in four genetic models. In summary, the present study suggests that IL-18 gene promoter 607A polymorphism is a protective factor for IS in the Chinese population, while 137C polymorphism has weaker or no protective properties. Still, a larger number of studies with large scale and sufficient original information are required to further confirm our findings.