Hyperactivity of the Na+/H+ exchanger in a mouse model of type 2 diabetic cardiomyopathy

DE FAZIO, RAYEN; ARRÍAS, PAULA N.; CARRIZZO VELASQUEZ, FERNANDA E.; JAQUENOD DE GIUSTI, CAROLINA

Rosario

Encuentro; Reunión anual de la SAFIS; 2019

Sociedad Argentina de Fisiología

Heart failure (HF) is the leading cause of death among diabetic people. Altered cellular ionbalance is related to HF. Hyperactivity of the Na + /H + exchanger (NHE1) has been related todisturbed cellular ion balance. Therefore, we have decided to study the role of NHE1 in thedevelopment of diabetic cardiomyopathy using ob -/- mice as obese and diabetic mice model andob +/- as controls. Our results indicated increased NHE1 activity in isolated myocytes from thehearts of ob -/- mice compared to ob +/- . Enhanced myocardial NHE1 activity could promote Na +and subsequently cytoplasmic Ca 2+ loading, leading to changes in mitochondrial Ca 2+ content. Wedetected altered Ca 2+ handlings in cardiac mitochondria of ob -/- mice. Mitochondria from ob -/-mice presented reduced swelling and Ca 2+ retention capacity. Also, these mitochondria presentedreduced membrane potential and increased membrane transition pore (mPTP) opening. All thesecould initially be explained by increased cardiac mitochondria Ca 2+ load. Additionally, wedetected increased NHE1 expression on mitochondrial membranes. NHE1 hyperactivity couldaffect mitochondria function by altering Na + content and affecting mitochondrial Na + /Ca 2+exchanger (NCLX) activity. In fact, NHE1 inhibition resulted in the reversion of this phenotype,indicating that the observed alterations could be due to increased NHE1 activity in ob -/- mice.Consistent with this hypothesis, these mitochondria also presented reduced Ca 2+ content. Thesefindings suggest that exacerbated NHE1 activity contributes to mitochondrial dysfunction, aprimary recognized pathogenic response in cardiovascular disease.