Myocardial ischemia reperfusion (I/R) can induce altered expression of microRNAs (miRNAs). The miRNAs-miR-15a, miR-15b and miR-16 have been shown to play a role in apoptosis, although not in cardiac-related models. We investigated the roles of miR-15b in hypoxia/reoxygenation (H/R)-induced apoptosis of cardiomyocytes. Quantitative real time polymerase chain reaction results showed that the expression of miR-15a and miR-15b were up-regulated in Sprague-Dawley rat hearts subjected to I/R. Expression levels of miR-15b increased more than four fold above basal levels. Similar results were obtained for cardiomyocytes exposed to H/R. Recombinant adenoviral vectors were generated to explore the functional role of miR-15b in cultured cardiomyocytes exposed to H/R. Overexpression of miR-15b enhanced cell apoptosis and the loss of mitochondrial membrane potential, as determined by flow cytometric analysis. Conversely, down-regulated expression was cytoprotective. The effects of miR-15b can by mimicked by Bcl-2 short-interfering RNAs. The inhibition of miR-15b increased expression levels of the Bcl-2 protein without affecting Bcl-2 mRNA levels, suppressed the release of mitochondrial cytochrome c to the cytosol and decreased the activities of caspase-3 and 9. It is possible that miR-15b is the upstream regulator of a mitochondrial signaling pathway for H/R induced apoptosis.

Background The efficacy and safety of nicorandil were evaluated in Chinese patients with stable angina pectoris (AP) in a double-blind, multicenter, active-controlled, randomized clinical trial. Methods and ResultsAfter a 2-week washout period, 232 patients with stable AP were randomized to receive either nicorandil (5 mg tid; 115 patients) or isosorbide mononitrate (ISMN: 20 mg bid; 117 patients) for 2 weeks. Exercise capacity, number of weekly anginal attacks, nitroglycerin (NTG) consumption, and safety were evaluated. Nicorandil and ISMN significantly prolonged the time to 1 mm ST-segment depression in an exercise tolerance test. Both drugs improved the total exercise time and the time to onset of chest pain. There was no significant difference between the 2 groups. Nicorandil significantly decreased the number of anginal attacks and NTG consumption. ISMN decreased the number of anginal attacks significantly; however, there was no significance in NTG consumption, and the ratio of anginal attack reduction was at least 50% was significantly higher with nicorandil. Nicorandil was well tolerated and there was no safety profile difference compared with ISMN. Thus, nicorandil may have equivalent or better antianginal effect than ISMN. Conclusions Nicorandil is beneficial as treatment for AP. (Circ J 2007; 71: 826 -833)

Introduction: It has been commonly accepted that second-hand smoke (SHS) is associated with atherosclerosis and endothelial dysfunction. There is growing evidence that the changes might begin in childhood. Unfortunately, no study has focused on the early atherosclerosis of Tibetan adolescents exposed to SHS. Aims: We aimed to investigate the endothelial function and carotid atherosclerosis in healthy school-aged Tibetan male adolescents. Materials and methods: All passive smoking participants (SHS) were students were 16 years old and male, and were recruited through middle schools in Lhasa city. In total 624 subjects were accepted after excluding subjects who actively smoked. The adolescents were divided into three groups according to serum cotinine level: high cotinine group (High Group) with 205 boys, intermediate cotinine group (Intermediate Group) with 210 boys, and low cotinine group (Low Group) with 209 boys. Venous blood was sampled for the measurement of cotinine concentration, lipid profile and endothelin-1 (ET-1) quantitation. High-resolution B-mode ultrasonography was performed to evaluate carotid intimamedia thickness (cIMT) and intima smoothness. The invasive vascular endothelial function was evaluated through the measurement of flow-mediated dilation (FMD) with B-mode ultrasound and ankle-brachial index (ABI) by using a blood pressure cuff and a Doppler instrument. Results: No statistical significance was found between groups in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, ApoA-I, systolic blood pressure, diastolic blood pressure, and heart rate (p>0.05). In the lipid profile, only apolipoprotein B (ApoB) values were different between groups: ApoB in the High Group was higher than in the Low Group (p=0.0164). Plasma ET-1 concentrations in the High Group were also much higher than in the Intermediate and Low Groups (p=0.0112, p<0.001). The cIMT and intima smoothness had deteriorated in the High Group compared with the Low Group (p<0.001 and p<0.05 respectively). FMD and ABI, which indicate vascular endothelial function, was decreased in the High Group compared with the Intermediate and Low Groups (FMD, p<0.001; ABI, p<0.001). Conclusions: SHS was associated with sub-clinical carotid atherosclerosis and endothelial dysfunction in Tibetan schoolaged male adolescents. Considering the widespread exposure to SHS and the clinical relevance of early atherosclerosis, this result is of public health importance in Tibet, where health education is not satisfactory. Data from our study emphasize the importance of endorsing smoke-free environments for adolescents.

Objective.To compare the level of expression of the renin-angiotensin-aldosterone system (RAAS) in mice with or without the endothelin-1 receptor antagonist bosentan and to examine the potential value in blood pressure regulation. Materials and methods. Bosentan (10 mg/kg/d) and placebo were given to two groups of male C57BL/6 mice (n=5) from ages 6 to 12 weeks. The mRNAs of liver, kidney and lung were isolated for Northern blot analysis. A further 15 male C57BL/6 mice were divided into three groups (n=5): mice in group A were given the angiotensin II type 1 receptor blocker valsartan (10 mg/kg/d); mice in group B were given bosentan (10 mg/kg/d); and mice in group C were given both valsartan and bosentan (10 mg/ kg/d for each drug). All mice were administered the drugs from 6 to 12 weeks of age and had their systolic blood pressure (SBP) measured at the end of the drug treatments.Results. Northern blot analysis demonstrated that the expression levels of angiotensinogen in liver (p=0.0126), renin in kidney (p=0.002), and angiotensin-converting enzyme in lung (p=0.0041) were upregulated in mice treated with bosentan. No difference in SBP was found among the groups before drug administration. Six weeks after monotherapy with valsartan, SBP was slightly lowered (126±2 vs. 122±3 mmHg, p=0.0381). Monotherapy with bosentan also had a small effect on SBP (126±2 vs. 122±3 mmHg, p=0.0381), whereas dual blockade with valsartan and bosentan significantly lowered SBP (127±3 vs. 103±3 mmHg, p<0.001). Conclusions. We conclude that RAAS components are upregulated under endothelin blockade. Dual blockade of the RAAS and endothelin system is beneficial for blood pressure control.

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The aim of the present study was to investigate whether a gradually increasing reperfusion algorithm, in which the brief reperfusion was lengthened as the duration of each reperfusion/reocclusion cycle remained fixed, enhances cardioprotection. Rats were randomized into 5 groups: the sham, reperfusion injury (R/I), gradually decreased reperfusion (GDR; 30/10‑25/15‑15/25‑10/30 sec of reperfusion/reocclusion), equal reperfusion (ER; 4 20/20‑sec reperfusion/reocclusion cycles) and gradually increased reperfusion (GIR; 10/30‑15/25‑25/15‑30/10 sec of reperfusion/reocclusion). The rats were sacrificed to measure serum markers, apoptotic indices and infarct size. Western blot analyses were used to analyze the expression of molecules involved in important signaling pathways. All the three postconditioning patterns were found to provide cardioprotection (P<0.05 compared with the R/I group). GIR provided optimum cardioprotection, followed by ER and then GDR. Apoptotic index and serum marker levels were significantly reduced in the GIR compared with the ER group (P<0.05). The enhanced cardioprotection provided by GIR was accompanied by significantly increased levels of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and Bcl‑2, as well as lower levels of p38/c‑Jun N‑terminal kinase (JNK) phosphorylation, tumor necrosis factor α (TNFα), caspase‑8, Bax, caspase‑9 and cytochrome c (Cyt‑c) in the cytoplasm of rats (P<0.05, all compared with ER). The infarct size in the rats of the GIR group was also smaller compared with that in the rats of the ER group, but this difference was not significant (16.30±5.22 vs. 20.57±6.32%, P>0.05). All the variables measured in the present study were significantly improved in the GIR group compared with the GDR group (P<0.05). In conclusion, the association between brief reperfusion and reocclusion is an important factor in postconditioning algorithms. Additionally, GIR results in improved cardioprotection compared with that achieved by the remaining algorithms examined.

Introduction: Resistin, an adipocyte-derived hormone, was found to be linked to metabolic syndrome and insulin resistance over the past decade. There is growing evidence that resistin plays a potential role in endothelial dysfunction. To the best of our knowledge, few studies have been concerned with the effect of resistin on endothelial function in a Tibetan population. Aims: To investigate the correlation of resistin and endothelial function among preclinical Tibetan male young adults. Materials and methods: All participants recruited were young adults between 30 and 40 years old of male gender in Lhasa city. All subjects were native Tibetan. A total of 90 healthy subjects were accepted after excluding hypertension, diabetes, hyperlipidemia or coronary artery disease. The subjects were divided into three groups according to flow-mediated dilation (FMD): lower FMD (group A), intermediate FMD (group B) and higher FMD (group C). Body mass index, systolic blood pressure (SBP), diastolic blood pressure (DBP) and cigarette smoking were evaluated. Venous blood was sampled for the measurement of lipid profile, fasting blood glucose (FBG), fasting insulin (FINS), endothelin-1 (ET-1) and plasma resistin quantitation. The non-invasive vascular endothelial function was evaluated through the measurement of FMD with B-mode ultrasound. The insulin resistance was estimated as homeostatic model assessment of insulin resistance (HOMA-IR) = FINS(mu/L)*FBG(mmol/L)/22.5. Results: No statistical significance was found between groups in age, smoking, SBP, DBP, fasting insulin, total cholesterol and HOMA-IR (p>0.05). In the lipid profile, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol in group C were better than in groups A and B (p<0.01). Body mass index, which is an indicator for obesity, was much lower in group C than in group A and B (p<0.05 and 0.01 respectively). Comparison of plasma resistin concentrations: group A > group B > group C (p<0.01). Comparison of plasma ET-1 concentrations had a similar result: group A > group B > group C (p<0.05). The multivariate regression analysis showed that total cholesterol (p<0.05), LDL cholesterol (p<0.01), plasma resistin (p<0.01) and plasma ET-1 (p<0.01) were correlated with FMD. Conclusions: Resistin is involved in endothelial dysfunction in preclinical male young Tibetan adults.

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