085 Thyroid hormone receptor alpha1 is down regulated during the progression to congestive heart failure after myocardial infarction

Abstract

Thyroid hormone (TH) signaling is altered in response to various stresses including myocardial ischaemia. The present study investigated potential implication of TH in the pathophysiology of postischaemic remodeling. Acute myocardial infarction was induced in rats by coronary artery ligation (AMI). After 34 wk, n = 6 animals were on congestive heart failure (CHF) as indicated by measurements in lung and right ventricular weight. N = 7 animals were in compensated state (non-CHF) and n = 8 SHAM operated animals served as controls (SHAM). Progression to congestive heart failure was characterized by marked decrease in EF% and all other functional echocardiographic parameters. Furthermore, β-MHC expression was significantly increased in CHF. A distinct pattern of TR expression was observed in the course of postischaemic remodeling; TRα1 was up-regulated and TRβ1 was down-regulated in non-CHF and TRα1 expression was markedly decreased during the transition from non-CHF to CHF resulting in tissue hypothyroidism. Circulating T3 and T4 remained unchanged. This response was associated with marked decrease in ERK and mTOR activation. A potential link between ERK, mTOR and TRα1 expression was shown in a neonatal cardiomyocytes model of PE (phenylephrine) induced pathological growth. PE increased the expression of TRα1 in nucleus and this response was abrogated after inhibition of mTOR or ERK. Progression to congestive heart failure after myocardial infarction is associated with suppressed expression of TRα1 and results in tissue hypothyroidism. This process may at least in part be mTOR and ERK dependent.