CONICET | Buscador de Institutos y Recursos Humanos

Heart failure is the leading cause of death among diabetic people. Cellular and molecular entities leading to diabetic cardiomyopathy (DCM) are poorly understood. The role of Na+/H+ exchanger 1 (NHE1) and Ca2+ load was studied in obese type 2 diabetic mice (ob-/-) and control heterozygous littermates (ob+/-).Echocardiography showed elevated systolic interventricular septum thickness and systolic posterior wall thickness in ob-/- mice at 16 weeks. ob-/- mice showed increased left ventricular weight/tibia length ratio and increased cardiomyocyte cross sectional area as compared to controls, indicating cardiac hypertrophy. Immunoblot analysis did not show altered NHE1 expression but augmented NHE1 phosphorylation in ob-/- hearts. NHE1-dependent rate of intracellular pH (pHi) normalization after acid loading of isolated cardiomyocytes was higher in ob-/- mice vs. ob+/-. Enhanced myocardial NHE1 activity could promote Na+ and subsequently cytoplasmic Ca2+ loading, leading to changes in mitochondrial Ca2+ content. We detected altered Ca2+ handlings in cardiac mitochondria of ob-/- mice. ob-/- mice presented reduced Ca2+ retention capacity, possibly due to increased cardiac mitochondria Ca2+ load. ob-/- mitochondria also presented altered membrane potential, a condition minimized by NHE1 inhibition. These findings suggest that exacerbated NHE1 activity contribute to mitochondrial dysfunction, a primary recognized pathogenic response in diabetic cardiomyopathic hearts.The mechanism by which NHE1 hyperactivity promotes cardiac hypertrophy and cardiac dysfunction in DCM has not yet been established. We proposed that elevation of cytosolic Ca2+ is the central hypertrophic signal in cardiomyocytes and also a signal for mitochondrial Ca2+ overload and subsequent mitochondrial dysfunction present in DCM hearts. We conclude that NHE1 activity is augmented in DCM of ob-/- mice, which may lead to perturbation of pHi and [Na+] and [Ca2+] handling in these diseased hearts.