Intermittent hypoxia has been shown to provide myocardial protection against ishemia/reperfusion-induced injury. Cardiac myocyte loss through apoptosis has been reported in ischemia/reperfusion injury. Our aim was to investigate whether intermittent hypoxia could attenuate ischemia/reperfusion-induced apoptosis in cardiac myocytes and its potential mechanisms. Adult male Sprague-Dawley rats were exposed to hypoxia simulated 5000 m in a hypobaric chamber for 6 h/day, lasting 42 days. Normoxia group rats were kept under normoxic conditions. Isolated perfused hearts from both groups were subjected to 30 min of global ischemia followed by 60 min reperfusion. Incidence of apoptosis in cardiac myocytes was determined by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and DNA agarose gel electrophoresis. Expressions of apoptosis related proteins, Bax and Bcl-2, in cytosolic and membrane fraction were detected by Western Blotting. After ischemia/reperfusion, enhanced recovery of cardiac function was observed in intermittent hypoxia hearts compared with normoxia group. Ischemia/ reperfusion-induced apoptosis, as evidenced by TUNEL-positive nuclei and DNA fragmentation, was significantly reduced in intermittent hypoxia group compared with normoxia group. After ischemia/reperfusion, expression of Bax in both cytosolic and membrane fractions was decreased in intermittent hypoxia hearts compared with normoxia group. Although ischemia/reperfusion did not induce changes in the level of Bcl-2 expression in cytosolic fraction between intermittent hypoxia and normoxia groups, the expression of Bcl-2 in membrane fraction was upregulated in intermittent hypoxia group compared with normoxia group. These results indicated that the cardioprotection of intermittent hypoxia against ischemia/reperfusion injury appears to be in part due to reduce myocardial apoptosis. Intermittent hypoxia attenuated ischemia/reperfusion-induced apoptosis via increasing the ratio of Bcl-2/Bax, especially in membrane fraction.

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Mountain sickness (MS) occurs among humans visiting or inhabiting high altitude environments. We conducted genetic analyses of the AKT3, ANGPTL4, eNOS3 and VEGFA genes in lowland (Han) and highland (Tibetan) Chinese. Ten single nucleotide polymorphisms (SNPs) were evaluated in Han and Tibetan patients with acute (A) and chronic (C) MS. We compared 74 patients with AMS to 79 Han unaffected with MS, as well as 48 CMS patients to 31 unaffected Tibetans. The ten SNPs studied are AKT3 (rs4590656, rs2291409), ANGPTL4 (rs1044250), eNOS3 (rs1007311, rs1799983) and VEGFA (rs79469752, rs13207351, rs28357093, rs1570360, rs3025039). Direct sequencing was used to identify individual genotypes for these SNPs. Hemoglobin (Hb), hematocrit (Hct), and red blood cell count (RBC) were found to be significantly associated with the AKT3 SNP (rs4590656), Hb was found to be associated with the eNOS3 SNP (rs1007311), and RBC was found to be significantly associated with the VEGFA SNP (rs1570360) in Tibetan patients with CMS. CMS patients were found to diverge significantly for both eNOS3 SNPs as measured by genetic distance (0.042, 0.047) and for the VEGFA SNP (rs28357093) with a genetic distance of 0.078 compared to their Tibetan control group. Heart rate (HR) was found to be significantly associated with the eNOS3 SNP (rs1799983) and arterial oxygen saturation of hemoglobin (SaO2) was found to be significantly associated with the VEGFA SNPs (rs13207351, rs1570360) in Han patients with AMS. The Han and Tibetan control groups were found to diverge significantly for the ANGPTL4 SNP and VEGFA SNP (rs28357093), as measured by genetic distances of 0.049 and 0.073, respectively. Seven of the SNPs from non-coding regions are found in the transcriptional factor response elements and their possible role in gene regulation was evaluated with regard to MS. AMS and CMS were found to be significantly associated with the four genes compared to their Han and Tibetan control groups, respectively, indicating that these nucleotide alterations have a physiological effect for the development of high altitude sickness.