THYROTROPIN MODULATES CALCIUM HANDLING AND CONTRACTILITY IN ADULT RAT CARDIAC MYO- CYTES

MARISA SEPULVEDA ; JULIETA FERNANDEZ-RUOCCO; JUAN IGNACIO BURGOS; CANDELA MARTINEZ; GABRIEL NEIMAN; MARIA AGUSTINA SCARAFIA; SANTIAGO GABRIEL MIRIUKA; ANDREA FELLET; EMILIANO MENDEI; MARTIN VILA PETROFF

Virtual

Congreso; LXV Reunion Anual de Sociedades de Biociencias; 2020

Sociedad Argentina de Investigacion Clinica (SAIC)

Hypothyroidism (Hypo) is associated with cardiac fibrosis, myocardial edema and contractile dysfunction. However, the subcellular mechanisms underlying contractile dysfunction are not completely understood. We hypothesized that an increase in the concentration of Thyrotropin (TSH), which occurs in the context of Hypo, could alter intracellular Ca2+ handling and contribute to the negative inotropic and lusitropic effects associated with Hypo. Our results show that TSH does not have direct acute effects on euthyroid adult cardiac myocyte contractility. However, when myocytes were exposed to TSH for 24 hours we observed a decrease in cellular contractility associated with a decrease in the amplitude and relaxation rate of the Ca2+ transient. A similar impact of TSH con contractility was observed in cardiomyocytes derived from human IPS cells. These effects were abolished by the PKA inhibitor H89, suggesting that the TSH receptor through its Gsa/PKA singling underlies the contractile effect of TSH in adult cardiac myocytes. Cardiomyocytes incubated with TSH showed profound alterations in the expression of Ca2+ proteins SERCA, RyR2 and the Na+/Ca2+ exchanger (NXC) which were reverted by H89. Importantly, TSH fails to further reduce contractility in myocytes isolated from a rat model of Hypo with elevated TSH. We conclude that TSH has direct negative effects on cardiac mechanical activity by altering the expression of Ca2+ handling proteins by a PKA-dependent-signaling pathway. We speculate that elevated TSH contributes to contractile dysfunction associated with Hypo.