[Effect of pioglitazone on arteria carotis remodeling in patients with metabolic syndrome].

OBJECTIVE: To observe the effect of pioglitazone on carotid artery intima-media thickness (IMT) and plaque-positive rate in patients with metabolic syndrome, and to find a new way to improve arterial remodeling in patients with metabolic syndrome. METHODS: Patients with metabolic syndrome were randomly divided into a control group (n=60) and a pioglitazone group (n=61). All subjects received basic therapeutic measures, i.e, appropriate medication to control blood pressure, blood sugar and cholesterol. Pioglitazone (15 mg/d) was given to patients in the pioglitazone group, and placebo (vitamin C) in the control group for 24 weeks. Color doppler ultrasound was used to measure carotid artery IMT and plaque-positive rate of patients in the 2 groups after the intervention. Japan's Hitachi 7600-020 automatic biochemical analyzer was used to measure fasting serumal triglycerides, total cholesterol, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, free fatty acids, fasting blood glucose, 2-hour postprandial glucose and liver and kidney function, etc. The differences between groups after the intervention were analyzed and compared in IMT, plaque-positive rate and all blood biochemical indicators. RESULTS: After the intervention, compared with the control group, carotid artery plaque-positive rate and the levels of triglyceride and free fatty acid decreased in the pioglitazone group (P<0.05), but there was no difference in IMT of carotid artery and other blood biochemical indicators between the 2 groups (P>0.05). CONCLUSION: Pioglitazone intervention can significantly improve pathologic artery remodeling, and it can more effectively inhibit the arterial plaque-formation than basic therapeutic measures in patients with metabolic syndrome.

The role of miR-145 in microvasculature.

Increasing evidence suggests that microRNAs(miRs) play a crucial role in the cardiovascular system, and recent studies have revealed a significant role of miRs in vascular biology and disease, miR-145 is one of the most-studied miRs, and especially in the vascular smooth muscle cell (VSMCs) proliferation, differentiation, and phenotypic switching. In cardiovascular system, miR-145 is not only important for heart and vascular development but also plays an essential role in cardiac pathological factors, such as hypertrophy, and ischemia. However, its potential role in microvasculature has not been systematically evaluated yet. We are just beginning to understand the regulation of miR in vascular biology. In particular, the miR biogenesis and regulatory pathways in the vascular system have not yet been well characterized, This review focuses on the basic biology and mechanism of action of miR-145 specifically pertaining to microvascular development, pericyte and disease, In addition it addresses the potential for miR-145 to be used therapeutically in the treatment of microvascular disease.

Soluble epoxide hydrolase inhibitors and cardiovascular diseases.

BACKGROUND: Epoxyeicosatrienoic acids (EETs) have been shown to play a role in cardiovascular protection by reducing ischemia reperfusion injury, producing anti-inflammatory effects, and promoting angiogenesis. EETs are regulated through conversion to less active corresponding diols by soluble epoxide hydrolase (sEH). Inhibition of sEH enhances the beneficial properties of EETs and has been investigated as a possible treatment for cardiovascular diseases. CONTENT: sEH inhibitors (sEHIs) have anti-inflammatory effects by stabilizing anti-inflammatory EETs. Additionally, sEHIs strongly inhibit and reverse cardiac hypertrophy. sEHIs have been shown to protect myocardial cells from ischemiareperfusion injury, treat atherosclerosis and prevent the development of hypertension. sEHIs promote blood vessels to release bradykinin via an EET-mediated STAT3 signaling pathway to elicit tolerance to ischemia. SUMMARY: Inhibition of sEH has been shown to improve several aspects of cardiovascular diseases, including inflammation, hypertension, cardiac hypertrophy and atherosclerosis. For this reason, sEHIs are promising new pharmaceutical for the treatment of cardiovascular diseases.

Biogenesis of MiRNA-195 and its role in biogenesis, the cell cycle, and apoptosis.

microRNA-195(miR-195) is an important member of the micro-15/16/195/424/497 family, and which is activated in multiple diseases, such as cancers, heart failure, and schizophrenia. Mir-195 regulates a plethora of target proteins, which are involved in the cell cycle, apoptosis, proliferation. WEE1, CDK6, and Bcl-2 are confirmed target genes of miR-195 that are involved in miR-195-mediated cell-cycle and apoptosis effects. However, the mechanism of miR-195 action is not completely understood. This review summarizes recent the research progress regarding the roles of miR-195 in the cell cycle and in apoptosis.

Fractalkine/CX3CR1 and atherosclerosis.

Fractalkine is a unique chemokine which has both adhesive and chemoattractant functions. With the increasing emphasis on the importance of inflammation in atherosclerosis, more attention has been focused on the role of chemokines in atherosclerosis. It has been shown that fractalkine/CX3CR1 participates in the atherosclerotic pathological process through mediating the recruitment of leukocytes and the interaction of vascular cells and leukocytes. Some signal pathways are simultaneously activated through fractalkine/CX3CR1 coupling to promote the inflammatory response in atherosclerotic vessels. Additionally, fractalkine has cytotoxic effects on endothelium as well as anti-apoptosis and proliferative effects on vascular cells which consequently changes plaque components and stability in plaque. Several studies have showed that fractalkine or CX3CR1 deficiency in atherosclerotic mice would ameliorate the severity of plaque. Population studies on CX3CR1 polymorphism have confirmed that 280M-containing haplotype is associated with reduced risk of atherosclerotic disease. Despite the apparent association with atherosclerosis, further studies on fractalkine/CX3CR1 chemokine pair are clearly warranted to more fully elucidate this relationship.

Aspirin inhibits fractalkine expression in atherosclerotic plaques and reduces atherosclerosis in ApoE gene knockout mice.

OBJECTIVE: To determine the fractalkine expression in the aorta of ApoE (-/-) mice and the effect of high-dose aspirin intervention on fractalkine expression and atherosclerotic lesion formation. METHODS: Twenty-one male ApoE gene knockout mice were randomized into three groups to receive either placebo in addition to normal mice chow (n = 7), placebo in addition to a high-fat diet (n = 7), or aspirin (58 mg/kg/d) in addition to a high-fat diet (n = 7). After 12 weeks of study, the mice were euthanized and serum cholesterol, thromboxane B(2), and 6-keto-PGF(1alpha) were examined. Fractalkine and cyclooxygenase expression in aorta were measured and the atherosclerotic lesion analyzed. RESULTS: Pathology image analysis showed that the atherosclerotic plaque was the most extensive in the high-fat diet group while the addition of aspirin greatly reduced the severity of the plaque. Both RT-PCR analysis and immunohistochemical analysis showed that fractalkine expression was the strongest in the high-fat diet group and was significantly decreased by aspirin treatment. Serum thromboxane B(2) was lowered by aspirin while 6-keto-PGF(1alpha) and cholesterol remained unchanged. CONCLUSIONS: The results of our study indicate that high dose aspirin can improve the atherosclerotic lesion and suppress the fractalkine expression in murine aorta.

[Effects of PPAR-gamma agonist rosiglitazone on MMP-9 and TIMP-1 expression of monocyte-derived macrophages isolated from patients with acute coronary syndrome].

OBJECTIVE: Coronary arterial plaque rupture and secondary thrombosis are the major pathogenesis of acute coronary syndrome (ACS). Metalloprotease (MMPs) secreted by monocyte/macrophage was the main predisposing factor of the plaque rupture and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is involved in a variety of inflammatory cytokine gene transcriptional regulations. We explored the possible role of PPAR-gamma in the regulation of MMP-9 and TIMP-1 expressed by peripheral monocyte-derived macrophages (MDMs) from patients with ACS. METHODS: Peripheral blood mononuclear cells were isolated from 48 patients with ACS and 28 healthy controls and stimulated by macrophage colony-stimulating factor (0.1 microg/ml for 24 hours) to form MDMs. MDMs were then incubated under various concentrations of rosiglitazone (0, 1, 10, 20 micromol/L) for 48 hours. The concentrations of MMP-9 and TIMP-1 in the supernatant were measured by enzyme linked immunosorbent assay, and the mRNA expression of PPAR-gamma, MMP-9 by RT-PCR and nuclear factor-kappaB P65 (NF-kappaB P65) expression by immunohistochemistry. RESULTS: PPAR-gamma mRNA expression was significantly lower while NF-kappaB P65 and MMP-9 expression as well as MMP-9 and TIMP-1 concentrations in supernatant were significantly higher in ACS group than those in control group (all P < 0.05). After rosiglitazone intervention, PPAR-gamma mRNA expression was significantly upregulated in both ACS and control groups in a dose-dependent manner. Both the MMP-9 concentration in the supernatant and MMP-9 mRNA expression were reduced post intervention with rosiglitazone in both groups. The TIMP-1 mRNA expression and concentration in supernatant were not affected by rosiglitazone in both groups. Rosiglitazone induced significant downregulation of NF-kappaB P65 expression in both groups. CONCLUSION: Rosiglitazone intervention may downregulate MMP-9 expression by upregulating PPAR-gamma expression, and by downregulating NF-kappaB expression in MDMs isolated from patients with ACS.

Aspirin inhibits tumor necrosis factor-alpha-stimulated fractalkine expression in human umbilical vein endothelial cells.

BACKGROUND: Fractalkine is an important chemokine mediating local monocyte accumulation and inflammatory reactions in the vascular wall. Aspirin inhibits inflammatory cytokine expression closely related to atherosclerosis through the way independent of platelet and cyclooxygenase (COX). There has been no report about the effect of aspirin on fractalkine expression. We aimed to determine the fractalkine expression in human umbilical vein endothelial cell (HUVEC) stimulated by tumor necrosis factor (TNF)-alpha and the effect of aspirin intervention. METHODS: Six of 8 HUVEC groups received either different concentrations of aspirin (0.02, 0.2, 1.0, 5.0 mmol/L) or 40 micromol/L pyrrolidinecarbodithioc acid (PDTC) or 0.5 micromol/L NS-398. The other two groups were negative control and positive control (TNF-alpha-stimulated). After being incubated for 24 hours, cells of the 8 groups except the negative control one were stimulated with TNF-alpha (4 ng/ml) for another 24 hours. After that, the cells were collected for RNA isolation and protein extraction. RESULTS: Both mRNA and protein expressions of fractalkine in HUVEC were upregulated by 4 ng/ml TNF-alpha stimulation. Aspirin inhibited fractalkine expression in a dose-dependent manner at mRNA and protein levels. Nuclear factor-kappa B inhibitor, PDTC, effectively decreased the fractalkine expression. Fractalkine expression was not influenced by COX-2 selective inhibitor NS-398. COX-1 protein expression was not changed by either TNF-alpha stimulation or aspirin, PDTC, NS-398 intervention. Both mRNA and protein expression of COX-2 in HUVEC were upregulated by 4 ng/ml TNF-alpha stimulation. Aspirin decreased COX-2 expression in a dose-dependent manner at mRNA and protein levels. CONCLUSIONS: TNF-alpha-stimulated fractalkine expression is suppressed by aspirin in a dose-dependent manner through the nuclear factor-kappa B p65 pathway.

Pioglitazone decreased CD40/CD40L expression on human umbilical vein endothelial cells induced by oxidized low-density lipoprotein.

BACKGROUND: The CD40/CD40 ligand pathway mediated inflammatory processes are important in atherogenesis and the formation of the intraplaque lipid pool. We tested the hypothesis that pioglitazone could decrease lectin-like oxLDL receptor-1 (LOX-1) and CD40/CD40L expression on human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein (oxLDL). METHODS: HUVECs were incubated with oxLDL for 24h with or without pretreated by pioglitazone. Expression of CD40/CD40L on the cell surface was detected by flow cytometry. CD40/CD40L and LOX-1 mRNA expression were evaluated by RT-PCR. The expression of LOX-1 on HUVECs was determined by cell immunohistochemistry. RESULTS: OxLDL increased the expression of CD40 and CD40L in a dose- and time-dependent manner. Pretreatment of HUVECs with pioglitazone (1 and 10 micromol/l) for 60 min decreased the expression of CD40 mRNA induced by oxLDL by 16% and 52%, respectively (both P<0.05). Pretreatment of HUVECs with pioglitazone (1 and 10 micromol/l) for 60 min decreased the expression of CD40L mRNA induced by oxLDL by 16% and 43% (both P<0.05). Also, pretreatment of HUVECs with pioglitazone (1 and 10 micromol/l) for 60 min also significantly decreased CD40 and CD40L expression on HUVECs induced by oxLDL in a concentration-dependent manner. Pretreatment of HUVECs with pioglitazone (1 and 10 micromol/l) decreased oxLDL induced upregulation mRNA of LOX-1 by 11% and 28%, respectively. Furthermore, through immunohistochemistry, we found that pioglitazone could decrease the LOX-1 expression on HUVECs induced by oxLDL. CONCLUSION: Pioglitazone inhibited the upregulation of LOX-1 on HUVECs elicited by oxLDL and subsequently decreased HUVECs CD40/CD40L expression induced by oxLDL. These observations provided novel insight into a potential novel anti-inflammatory pathway of thiazolidinediones.

Changes in serum interleukin-6 and high-sensitivity C-reactive protein levels in patients with acute coronary syndrome and their responses to simvastatin.

The role of inflammation in acute coronary syndrome (ACS) and the mechanism by which statin treats ACS is explored. Serum high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) levels were measured in 50 patients with ACS [including 30 cases with unstable angina (UA) and 20 patients with acute myocardial infarction (AMI)], 34 patients with stable angina (SA), and 30 controls. Patients in the ACS group were randomly assigned to a simvastatin group (including a simvastatin AMI subgroup, n = 11 and a simvastatin UA subgroup, n = 14) and a routine group (including a routine AMI subgroup, n = 9 and a routine UA subgroup, n = 16). The simvastatin group was given simvastatin 20mg/day and the routine group a placebo. After a 3-week follow-up, serum hs-CRP, IL-6 levels, and serum lipid concentrations were measured again. Both serum IL-6 and hs-CRP levels were significantly higher in the ACS group (including the UA and AMI subgroups) than in the SA and control groups (P < 0.001). After 3 weeks of treatment with simvastatin, the serum IL-6, hs-CRP, total cholesterol, and low-density lipoprotein cholesterol levels were decreased significantly in the simvastatin group (P < 0.001), but no significant changes were observed in the routine group. No relationship was observed between the rate of decrease of serum IL-6 or hs-CRP and serum lipids levels. The hs-CRP level showed a significant correlation with IL-6 by Spearman's rank correlation analysis (P < 0.01). Inflammation plays an important role in the initiation of ACS. Simvastatin possesses an anti-inflammatory effect, independent of its lipid-lowering action, which may play an important role in the early treatment of ACS.