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Many studies have suggested that VSMC (vascular smooth muscle cell) apoptosis plays a key role in destabilization and rupture of atherosclerotic plaques. Therefore protection for VSMCs from apoptosis is a promising approach to stabilize 'vulnerable' lesions. However, the mechanisms as to why VSMCs in the fibrous cap often appear as profilerated in early stages, but turn apoptotic in advanced stages, are still unknown. In the present study, using RNAi (RNA interference) technology and a CaN (calcineurin) antagonist, the correlation between CaN and RANTES (regulated upon activation, normal T-cell expressed and secreted) in cultured rat apoptotic VSMCs stimulated by IFNgamma (interferon gamma; 20 ng/ml) and CD40L (CD40 ligand; 100 ng/ml) was investigated. RANTES released from VSMCs in each group was measured by ELISA and its mRNA in VSMCs was determined by RT (reverse transcription)-PCR. The total activity and expression of CaN in VSMCs were detected by the zymochemistry method and Western blot analysis respectively. From the results of the present study it can be hypothesized that an elevated CaN concentration in endochylema, by the CD40-CD40L signal pathway, induces VSMC apoptosis accomplished by the overexpression of RANTES. Therefore RANTES is a potential target for treating vulnerable atherosclerotic plaques owing to its crucial downstream regulating role in CaN-dependent VSMC apoptosis.

Background Ketanserin (KT), a selective serotonin (5-HT) 2-receptor antagonist, reduces peripheral blood pressure by blocking the activation of peripheral 5-HT receptors. In this study electrophysiological method was used to investigate the effect of KT and potassium ion on Kv1.3 potassium channels and explore the role of blocker KT in the alteration of channel kinetics contributing to the potassium ion imbalances. Methods Kv1.3 channels were expressed in xenopus oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. Results KCI made a left shift of activation and an inactivation curve of Kv1.3 current and accelerated the activation and inactivation time constant. High extracellular [K + ] attenuated the blockade effect of KT on Kv1.3 channels. In the presence of KT and KCI the activation and inactivation time constants were not influenced significantly no matter what was administered first. KT did not significantly inhibit Kv1.3 current induced by tetraethylammonium (TEA). Conclusions KT is a weak blocker of Kv1.3 channels at different concentrations of extracellular potassium and binds to the intracellular side of the channel pore. The inhibitor KT of ion channels is not fully effective in clinical use because of high [K + ] o and other electrolyte disorders.

Angiographically visible complex lesions, associated with disrupted plaques and intraluminal thrombus, are more common in unstable angina (UA). The aim of our study was to evaluate the relationship between the complex lesions and the T helper cells related Interleukins (IL). We analyzed the concentrations of IL-10, IL-12, IL-18 using ELISA and that of hsCRP using Latex particle enhanced Immunoturbidimetry in 50 patients of UA. Thirty-one of these patients had complex lesions and 19 had simple lesions as visible during coronary angiography. We further compared them with 30 control subjects having no evidence of coronary artery diseases. The levels of IL-12 in patients having complex lesions tended to be higher than in those having simple lesions and levels of IL-10 tended to be lower in the former than the latter, but the differences were not statistically significant. The patients with complex lesions showed significantly higher concentrations of IL-18 as compared to those having simple lesions. Furthermore, IL-18 was found to be independent predictor for the complex lesion morphology in UA patients. These findings suggest that disrupted plaques and intraluminal thrombus, angiographically visible as complex lesions are associated with increased concentrations of T helper 1 cell related interleukins, mainly IL-18, and IL-18 being a possible bio-marker for risk stratification in UA.

Objective The objective of this study was to investigate the effect of simvastatin on TLR4,TNF-alpha and IL-6 expression in the myocardium and its relation to left ventricular (LV) remodelling in a rat model of myocardial infarction (MI) and to investigate the mechanism by which simvastatin improves LV remodelling in rats after MI. Methods and results The rat MI models were established by ligation of the left anterior descending coronary artery and divided into three groups: (I) an untreated MI group; (2) a group treated with simvastatin [40 mg/(kg/d)] for 4 weeks; (3) the sham group. Cardiac geometry and function were determined by echocardiography and infarct size was determined by the histomorphometric analysis; the expression ofTLR4 in the myocardium was measured by RT-PCR and western blotting;TNF-alpha and IL-6 levels in myocardial homogenate and serum were measured by ELISA. LVEDD and LVESD significantly increased and fractional shortening (FS) markedly decreased in the MI group. It was clear that simvastatin inhibited LV dilation and improved LV function after MI without affecting infarct size. The expression of TLR4, TNF-alpha and IL-6 in the myocardium significantly increased in the MI group and simvastatin markedly inhibits the expression of TLR4, TNF-alpha, and IL-6 in the myocardium after MI. Serum TNF-alpha and IL-6 levels between the MI group and the simvastatin group remained unchanged. Both in the MI group and the simvastatin group,TLR4 protein positively related to LVEDD and to the levels of TNF-alpha and IL-6 in the myocardium, respectively. Conclusion Amelioration of LV remodelling in rats after MI by simvastatin might be associated with its effect on the TLR4-mediated signalling pathway in the myocardium.

Adiponectin, an adipocyte-specific protein, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a crucial role in arteriosclerosis and plaque disruption. The present study was designed to elucidate the relationship of adiponectin and the ratio of MMP-9/TIMP-1 and their effects on the stability of plaque in acute coronary syndrome (ACS).The concentrations of adiponectin, MMP-9, TIMP-1 and interleukin-10 were analyzed using ELISA in 56 consecutive unselected patients divided into two groups, stable angina (n=13) and ACS (n=43), and were compared with 19 healthy control subjects. The 56 patients were also angiographically studied and divided into two groups, simple lesion (n=22) and complex lesion (n=34), based on coronary plaque morphology.The ratio of MMP-9/TIMP-1 showed significantly higher values in the ACS group compared with the control group (0.22+/-0.10 versus 0.11+/-0.03; P0.001). Adiponectin was negatively correlated with the ratio of MMP-9/TIMP-1 (r=--0.332; P=0.008) and positively correlated with interleukin-10 (r=0.651; P=0.001). Multivariate logistic regression analysis showed that adiponectin (P=0.046) and MMP-9/TIMP-1 (P=0.044) are independent predictors for ACS, and MMP-9/TIMP-1 (P=0.013) is an independent predictor for complex lesion morphology plaques.In the present study, it was found that adiponectin has a negative relationship with the ratio of MMP-9/TIMP-1 in patients with ACS, and that the ratio of MMP-9/TIMP-1 is an independent predictor of the stability of atherosclerotic plaque and the severity of coronary atherosclerosis.

The novel chemokine CXCL16 is involved in the development of atherosclerosis and coronary artery disease (CAD). However, the role of CXCL16 in atherosclerosis remains uncertain. This study was designed to investigate the relationship between CXCL16 and the severity of coronary artery stenosis.Using ELISA, we assayed the plasma CXCL16 concentration in 16 stable angina pectoris (SAP) patients, 53 acute coronary syndrome (ACS) patients, and 19 control patients. All patients underwent coronary angiography after admission. They were divided into four groups according to the quartile of CXCL16 level. Characteristics and the relationship between CXCL16 and the elements were studied in each group.CXCL16 levels in the ACS group were higher than controls and SAP group (p0.01 vs. controls; p0.05 vs. SAP group). Gensini score in the highest quartile group of CXCL16 level (group IV, CXCL162.21 ng/mL) was significantly higher than in the lowest quartile group of CXCL16 level (group I, CXCL16or = 1.43 ng/mL) (p0.001). Gensini score in group II (1.43 ng/mLCXCL16or = 1.72 ng/mL) and group III (1.72 ng/mLCXCL16or = 2.21 ng/mL) were also higher than in group I (p0.05, p0.01). In addition, CXCL16 level had a positive correlation with Gensini score (r = 0.519, p0.001).CXCL16 levels are positively associated with the severity of coronary artery stenosis. Activity level of CXCL16 in human plasma appears to be a good biomarker for epidemiological and clinical application in CAD.

Atherosclerosis is a chronic inflammatory disease and interleukins are considered to play a key role in the chronic vascular inflammatory response that is typical of atherosclerosis. The serum levels of several of these cytokines have been found to positively correlate with coronary arterial disease and its sequelae.The aim of our study was to evaluate the levels of a comparatively new cytokine IL-17, in patients with stable and unstable coronary artery disease in order to assess whether unstable coronary artery disease patients had higher IL-17 levels.We analyzed the concentrations of IL-17, IL-6, IL-8 and IL-10 using enzyme-linked immunosorbent assay and heat-sensitive C-reactive protein using latex particle-enhanced immunoturbidimetry in 58 consecutive unselected patients divided into three groups: stable angina (n=14), unstable angina (n=24) and acute myocardial infarction (n=20). We further compared them with 20 healthy controls. These 58 patients were also angiographically studied and divided into two groups: simple lesion (n=22) and complex lesion (n=36), on the basis of the coronary plaque morphology.Our results show increased concentrations of the proinflammatory cytokines IL-17, IL-6, IL-8 and heat-sensitive C-reactive protein, and decreased concentration of IL-10 in plasma of unstable angina and acute myocardial infarction patients. Plasma concentration of IL-17 was also positively correlated with plasma concentrations of IL-6 and heat-sensitive C-reactive protein. Our findings further showed that IL-17 values were higher in patients having angiographically visible complex types of lesions but no difference was observed between complex and simple lesion morphology patients.In conclusion, these findings point towards a role of inflammation in the form of increased activity of IL-17, IL-6 and IL-8 in patients of unstable angina and acute myocardial infarction and thus suggest that IL-17-driven inflammation may play a role in the promotion of clinical instability in patients with coronary artery disease.

This study aimed to investigate the effects of folate on the monocyte chemoattractant protein-1 (MCP-1) expression and release in rats with hyperhomocystinemia induced by ingestion of excess methionine.Thirty male Sprague-Dawley rats (200+/-20 g) were randomly divided into three groups (n=10 for each group): control group (Control), high-homocystinemia (Hhcy) group, and folate treatment (FA) group. They were fed with a normal regular diet, enriched by 1.7% methionine plus 1.7% methionine and 0.006% folate for 45 days. Our study showed the following: (a) A high methionine diet for 45 days is sufficient to induce hyperhomocystinemia; folate supplementation to the rats fed the high-methionine diet prevented an elevation homocysteine (Hcy) levels in the blood (P.01). (b) Compared with the Control group, the Hhcy group had elevated plasma levels of MCP-1, and Hcy was significantly correlated with MCP-1 (P.05). (c) The protein and mRNA expression of MCP-1 in the aorta was higher in rats from the Hhcy group than in rats from the Control group. (d) Most important, after folic acid supplementation, the lowering of Hcy levels was accompanied by a marked reduction of MCP-1 expressed in aortae and released from plasma and peripheral blood mononuclear cells (PBMCs) stimulated by oxidized low-density lipoprotein (P.05, P.01).Folic acid supplementation not only can blunt the rise in Hcy and reduce MCP-1 released from both plasma and PBMCs of rats with hyperhomocystinemia but also can downgrade MCP-1 expression in the aorta of rats with hyperhomocystinemia.