Antiapoptotic Effect Of Metabolism Pathway Intervention In Hypertrophied Cardiomyocytes

Many studies have shown that apoptosis gets involved in the mechanisms that myocardium hypertrophy transfers to heart failure, and plays a important role in pathologic injury caused by ischemia-reperfusion. Recently, apoptotic biochemical process and signal transduction has been clarified, that is to say ,apoptotic pathway mediated either by mitochondria or death receptors activate caspase cascade to induce cell apoptosis. The mechanism that apoptosis regulated by mitochondria is widely supported.Myocardium is a kind of tissue with active energy metabolism, and containing abundant mitochondria. Mitochondial chief function is energy metabolism, which plays a vital role in maintenace of cellular physiological functions. Recent studies indicated that mitochondria were tightly related with cell apoptosis, and possessed function of regulating apoptosis. Abnormalities of mintochondrial metabolism includes alteration of energy metabolism pathways and injury of electron transport chain, but their relationship with apoptosis is undiscovered. When hypertrophied, myocardium energy metabolic model markedly change. In hypertrophied heart, fatty acid oxidation(FAO) is severely depressed, and glucose oxidation is enhanced, and cardiac FAO enzyme gene expression is shown to be coordinately downregulated and consistent with reinduction of the fetal energy metabolic program. The mechanisms that energy substrate preference switch from fatty acid to glucose may be related with many elements, including chronic ischemia and hypoxia ,and alteration of concentration of cellular factors related with regulating metabolism and level of enzyme phosphorylation, but the deactivation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARaha) and its coactivator the PPARgamma coactivator 1 (PGC-1) complex plays a pivotal role in the control of cardiac mitochondrial number and function. The deactivation of PPARalpha and PGC-1 during the development of cardiac hypertrophy involves regulation at several levels, including a reduction in the expression of these genes, as well as post-translational effects due to the mitogen-activated protein kinase (MAPK) pathway. The mechanisms of deactivation of PPARalpha/PGC-1 complex remain to be fully elucidated. Recent studies indicate that energy metabolic disfunction was associated with myocardium hypertrophy and heart failure, and think abundant oxygen-derived free radidicals due to abnormality of mitochondrial electron transport chain cause cell apoptosis. mitochondrial energy metabolism relies mostly on FAO and glucose oxidation. Under physiological condition, all kinds of intersubstrate can be metabolized completely by their mutual regulation, but during ischemia and hypoxia, inhibition of some inter-link causes detrimental substance accumulation. Alteration of mitochondrial energy metabolic pathways may be associated with injury of myocardium. At clinical, the therapy that activates glucose oxidation and inhibites FAO brings beneficial effect to cardiac angina. But it is not clear that either whether activation of FAO induces apoptosis, or activation of glucose oxidation inhibites apoptosis, and not known whether the drugs activating glucose oxidation or inhibiting FAO can inhibite apoptosis. To clarify these questions is of important significance in preventing myocardium hypertrophy to or delaying it to heart failure.To explore the mechanism by which mitochondrial energy metabolic pathway switchs from FAO to glucose oxidation and FAO is activated during ischemia and hypoxia in hypertrophied heart, and to clarify relationship between alteration of mitochondrial metabolic pathways and cell apoptosis, we isolated and cultured cardiomyocytes, and induced them to be hypertrophied. Hypertrophied cardiomyocytes cultured during hypoxia reoxygenation. We detected apoptotic rate and energy metabolism of cardiomyocytes during reoxygenation, and measured activity of PDH and CPT, glucose oxidation and FAO when glucose metabolism or fatty acid metabolism was activated or inhibited .