ABSTRACT
Exposure to systemic hypoxia induces cardiac adaptive responses similar to ischemic preconditioning. However, the subcellular mechanisms involved in hypoxic preconditioning are still unclear. We therefore, tested the role of hypoxia sensitive agents such as VEGF and erythropoietin in mediating hypoxic preconditioning in response to acute intermittent hypoxia. 48 male Wistar rats were randomly assigned into normoxic nx group [n=12], kept in normoxic conditions, Acute intermittent hypoxia AIH group [n=12] subjected to brief cycles [5 min] hypoxia/reoxygenation for one hour hearts from both groups were isolated 24 hours later perfused in a retrograde manner in Langendorff apparatus and subjected to in vitro global ischemia for 30 mins followed by reperfusion. The following parameters were measured at baseline, during and at the end of 120 min reperfusion: Left ventricular developed pressure [LVDP]; left ventricular end diastolic pressure [LVEDP]; rate pressure product [RPP]; peak left ventricular pressure rise [AP/At max] and heart rate [HR] At the end of reperfusion hearts were collected for subsequent reverse transcriptase polymerase chain reaction [RT PCR] and immu-histochemical analysis for VEGF and Erythropoietin. AIH 3 [n=12], AIH8 [n=12] groups, were subjected to one hour brief cycles [5 min] hypoxia reoxygenation as described above, were then sacrificed after 3, 8 hours [respectively], Hearts were collected for studying the time course for the expression pattern of VEGF and erythropoietin: Hearts of AIH displayed a significant improvement in postischemic hemodynamic measures compared to controls, indicated by higher LVDP [76% recovery versus 39% in nx], RPP [76% recovery versus 38%] and AP/At [66% recovery versus 43%]. AIH caused a significant increased expression of VEGF and Epo by cradiomyocytes. This increased expression was detected at 3 and 8hrs [AIH3, AIH8] denoting early induction of VEGF and Epo genes by acute intermittent hypoxia. Increased expression of VEGF and Epo genes was also detected 24 hours [AIH] following hypoxic exposure. Exposure of rat hearts to acute intermittent systemic hypoxia confers cardioprotective effects. This was evident by improved cardiac performance following ischemia reperfusion. The improved postischmeic cardiac function was associated with rapid induction of VEGF and erythropoietin by cardiac cells that lasted for 24 hours later, therefore theses cytokines appear to play a role in mediating early and delayed cardiac adaptive responses to acute intermittent hypoxia. Hypoxic training could thus provide a new approach to enhance endogenous cardioprotective mechanisms