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 swelling and Ca2+ retention capacity. In addition, these mitochondria presented reduced membrane potential. All these could be initially explained by increased cardiac mitochondria Ca2+ load. However, we detected increased NHE1 expression on mitochondrial membranes, NHE1hyperactivity could affect mitochondria function by altering Na+ content and affecting NCX activity. In fact, NHE1 inhibition resulted in reversion of this phenotype, indicating that the observed alterations could be due to increased NHE1 activity in ob-/- mice. These findings suggest that exacerbated NHE1 activity contributes to mitochondrial dysfunction, a primary recognized pathogenic response in diabetic cardiomyopathic hearts.