The herbal extract HMC05 inhibits neointima formation in balloon-injured rat carotid arteries: possible therapeutic implications of HMC05.

AIM OF THE STUDY: In a previous study, HMC05, a water extract from eight medicinal herbs was demonstrated to possess anti-inflammatory effects in murine macrophages and anti-atherosclerotic effects in apoE(-/-) mice. HSP27 expression was shown to be decreased in advanced atherosclerotic plaques of human carotid arteries. In the present study, the role of HMC05 in the prevention of restenosis and the possible mechanisms involved in the decrease of neointima formation were investigated using in vivo balloon injury rat model and in vitro biochemical assays. MATERIALS AND METHODS: A rat carotid artery balloon injury restenosis model was used. Different doses of HMC05 were administered to the rats by tube feeding, starting from four days before surgery and continuing twice per week for two weeks after carotid injury. Injured carotid arteries isolated from rats were embedded in paraffin block and tissue sections were stained with H&E to assess neointima formation. Mechanism by HMC05 that are involved in smooth muscle cell proliferation and migration was assessed by western blot assay, immunohistochemistry and confocal analysis. RESULTS: There was no significant difference in the medial area between the control and HMC05-treated groups. However, neointima formation was significantly inhibited in the HMC05-treated group, resulting in 47-fold lower intima to media ratios in rats treated with 25 mg/kg/day HMC05 as compared to the control. Surprisingly, monocytes infiltration in the neointima area was almost completely blocked by HMC05 administration. When rat vascular SMCs were treated with HMC05, the proliferation and migration of smooth muscle cells was dramatically inhibited in a dye uptake assay and in a scratch model in a culture dish, respectively. HMC05 dose-dependently inhibited PDGF-mediated MAPK and AKT activation. However, HMC05 did not affect PDGF-mediated HSP27 phosphorylation but it induced HSP27 overexpression and phosphorylation. In addition, medial SMCs in the arterial wall of rats treated with HMC05 showed a significant increase in HSP27 expression compared with that of the control rats. CONCLUSIONS: HMC05, a strong anti-inflammatory reagent, might use HSP27 as an effector molecule in SMCs to reduce neointimal hyperplasia by inhibiting PDGF-mediated MAPK and AKT activation. HMC05 could be a useful drug candidate for the prevention of restenosis after balloon injury of the arteries.

Validation of the association between AGTRL1 polymorphism and coronary artery disease in the Japanese and Korean populations.

Coronary artery disease (CAD) and stroke are the major health problems in many countries because of their increasing prevalence and high mortality. It is well known that CAD and stroke are based on atherosclerosis and shared environmental and genetic risk factors. Recently, an association of a functional sequence variation -154G>A in the angiotensin receptor-like 1 (AGTRL1) with a susceptibility to stroke was reported. In this study, we investigated a total of 1479 CAD cases and 2062 controls from the Japanese and Korean populations to validate the association of AGTRL1 with CAD. However, we obtained no evidence of the association in both the Japanese (odds ratio (OR)=0.95, 95% confidence interval (CI); 0.82-1.10, P=0.47, allele count model) and Korean (OR=0.90, 95% CI; 0.77-1.05, P=0.18, allele count model) populations. In addition, there was no trend of association between the risk allele and severity of coronary atherosclerosis. These data suggested that AGTRL1 did not contribute much to the atherosclerosis of the coronary artery.

Replication of the association between a chromosome 9p21 polymorphism and coronary artery disease in Japanese and Korean populations.

Coronary artery disease (CAD) has become a major health problem in many countries. Recent genome-wide association studies have identified the association between rs1333049 on chromosome 9p21 and susceptibility to CAD in Caucasoid populations. In this study, we evaluated the associations of rs1333049 with CAD in Japanese (604 patients and 1,151 controls) and Koreans (679 patients and 706 controls). We found a significant association in both Japanese [odds ratio (OR)=1.30, 95% confidence interval (CI); 1.13-1.49, p=0.00027, allele count model] and Koreans (OR=1.19, 95% CI; 1.02-1.38, p=0.025, allele count model). These observations demonstrated that chromosome 9p21 was the susceptibility locus for CAD also in East Asians.

Four SNPs on chromosome 9p21 in a South Korean population implicate a genetic locus that confers high cross-race risk for development of coronary artery disease.

OBJECTIVE: Recent genome-wide association studies have identified 4 SNPs on chromosome 9p21 associated with CAD (rs10757274 and rs2383206) and myocardial infarction (MI: rs2383207 and rs10757278) in White populations in Northern Europe and North America. We aimed to determine whether this locus confers significant susceptibility to CAD in a South Korean population, and thus cross-race susceptibility to CAD. METHODS AND RESULTS: We performed a case-control association study with 611 unrelated CAD patients and 294 normal controls from South Korea. Allelic associations of SNPs and SNP haplotypes with CAD were evaluated. Multivariate logistic regression analysis was used to adjust effects of clinical covariates. We found that 4 SNPs on chromosome 9p21 were associated with susceptibility to CAD in a South Korean population. The association remained significant after adjusting for significant clinical covariates (P=0.001 to 0.024). We identified one risk haplotype (GGGG; P=0.017) and one protective haplotype (AAAA; P=0.007) for development of CAD. Further analysis suggested that the SNPs probably confer susceptibility to CAD in a dominance model (covariates-adjusted P=0.001 to 0.024; OR=2.37 to 1.54). This represents the first study that expands association of these 9p21 SNPs with CAD beyond White populations. CONCLUSIONS: Chromosome 9p21 is an important susceptibility locus that confers high cross-race risk for development of CAD.