Abstract 3556: Inhibition of Mitochondrial Na+/Ca2+ Exchanger Improves Energy Supply in Heart Failure
Heart failure is associated with increased intracellular Na+ ([Na+]i) level. Our previous work demonstrated that elevated [Na+]i impaired mitochondrial NADH production in cardiomyocyte by inhibiting mitochondrial Ca2+ ([Ca2+]m) accumulation, which suggested detrimental effects of increased [Na+]i on mitochondrial bioenergetics in failing heart. In the present work, we investigated i) whether NADH/NAD+ balance is impaired in cardiomyocytes from failing heart, ii) whether decrease of [Na+]i or treatment of CGP-37157, an inhibitor of mitochondrial Na+/Ca2+ exchanger, improves NADH production in cardiomyocytes from failing heart by using a heart failure model. Ascending aortic constriction was applied to 250 –300g male guinea pigs. Cardiomyocytes were isolated at 6 – 8weeks when decreases of ejection fraction (EF) were observed. Compared to age-matched non-surgical controls, heart weight/tibia length of aortic banding animals was increased by ~85%. EF of banding hearts was decreased by 20%. [Na+]i, indicated by SBFI, was increased in failing hearts compared to controls (from 5.22±1.36 to 16.81±3.13 mM). Cardiomyocytes were superfused with Tyrode’s solution containing 2mM Ca2+ and 100nM isoproterenol with or without 10mM CGP-37157. Mitochondrial NADH, expressed as percentage of reduced NADH pool, was recorded at rest and during 4Hz stimulation, followed by a return to the resting state. In normal cardiomyocytes, NADH level was maintained during 4Hz stimulation. However, in most cardiomyocytes from failing heart, NADH levels decreased dramatically (~35%) during stimulation. CGP-37157 recovered NADH production of cells from failing heart during stimulation and decrease of [Na+]i by patch clamp with 5mM Na+ in pipette solution also prevented the impaired NADH response in heart failure. Decrease of [Na+]i to 5mM also enhanced [Ca2+]m accumulation while compared to that of cells patch clamped with 15mM Na+. We conclude that high intracellular Na+ level in heart failure impairs mitochondrial bioenergetics, and this impairment can be prevented by inhibiting the mitochondrial Na+/Ca2+ exchanger. The findings support our hypothesis that mitochondrial Na+/Ca2+ exchanger is a potential therapeutic target to improve the function of failing heart.