Role of Rac1 in Thyroxin-Induced Cardiovascular Abnormalities

Abstract

Development of cardiac hypertrophy (CH) after thyroxin (T4) treatment is well established. Many signaling pathways have been implicated in this phenomenon such as PI3K, PKB/Akt, or the rennin-angiotensin system. Recently, we observed that T4-induced CH is associated with increased cardiac Rac1 expression and activity. Whether these increases have a role in inducing this cardiac outcome still unknown. Here, we showed that T4 treatment (500 μg/kg/day) for two weeks resulted in CH and hypertension in mice. Left ventricular systolic function is also decreased in these mice compared to WT. Under near physiological conditions, right ventricular papillary muscles of T4-treated mice maintained their peak isometric active developed tension, but exhibited significant decreases in their corresponding time to peak, 50% relaxation, and 90% relaxation times. Positive inotropic responses to increasing heart rate (frequency) and β-adrenergic stimulation were markedly depressed in these muscles compared to WT. Rac1 inhibitor, pravastatin (10 mg/kg/day) significantly decreased the T4-induced hypertension but not the CH or any of the T4-induced contractile changes in cardiac muscles. In conclusion, T4 induces different signaling pathways with different cardiac outcomes. Rac1 seems to play a role in T4-induced hypertension with a minor involvement in T4-induced CH. Contractile abnormalities of cardiac muscles after T4 treatment are apparently dependent on CH but not hemodynamic changes (elevated blood pressure). Early treatment of T4-induced CH could represent a valuable therapeutic strategy to prevent progression to heart failure in hyperthyroid patients.