Endocrine Abstracts

Ischemic heart disease (IHD) is one of the leading causes of death worldwide. TH have impact on cardiac function and even appear to improve outcome after acute ischemia/reperfusion and in chronic heart failure. This project aims to investigate the influence of TH receptor alpha (TRα) on IHD using specific mouse models to assess the contribution of canonical vs. non-canonical TH signaling. Mice underwent permanent ligation of the left descending coronary artery and were treated with 500 ng/ml T3 for 8 weeks. To evaluate the impact of the different TH signaling pathways, we used wild type (WT), TRα knockout (TRαKO) and knock-in mice with a mutation that abrogates canonical TRα signaling (TRαGS). Cardiac function was assessed by echocardiography, remodeling assessed by histological staining (HE/SR). Serum TH levels were analyzed by ELISA. Contractile parameters and cardiomyocyte (CM) hypertrophy were analyzed using isolated adult CM from WT, TRαKO and GS mice or neonatal mouse CM (NMCM). Cardiac vascularization was detected by anti-CD31 immunohistochemistry. Heart weight and CM size were increased in T3 treated WT mice. Echocardiography and histological analyses revealed reduced fibrosis in the remote area and reduced infarct size in response to T3. Total cardiac vessel number increased with T3 and proportional to heart weight, indicating T3-induced neoangiogenesis. Comparison of untreated WT, TRαKO and GS hearts suggests that this effect originates from noncanonical TRα signaling as GS mice had the highest total cardiac vessel length among the genotypes. In vitro analyses using CM suggest significant differences in contractility with reduced maximal sarcomere shortening of TRαKO and GS compared to WT. As observed in vivo, hypertrophic growth of NMCM was induced by T3. We show that T3 is indeed cardioprotective with improved infarct size. Current experiments will further reveal how canonical and noncanonical TRα signaling is involved in these T3 mediated cardioprotection.