Endocrine Abstracts

Background: Ischemic heart disease (IHD) is one of the leading causes of death worldwide. Thus, there is the necessity to find new therapeutic approaches. Thyroid hormones (TH) have a major impact on cardiac function and even appear to improve the outcome after acute ischemia/reperfusion and in chronic heart failure. Still, TH signaling within the heart is not yet completely understood.

Aim: This project aims to investigate the influence of TH receptor alpha (TRα) on IHD using specific mouse models that allow to evaluate the contribution of canonical and non-canonical TH signaling (DNA-binding and regulation of gene expression vs. signaling pathway activation, respectively).

Methods: 8-10-week-old C57BL/6J mice underwent permanent ligation of the left descending coronary artery (LAD) and were treated p.o. with 250, 500 or 750 ng/ml T3 for 8 weeks directly after surgery to evaluate the optimal T3 dosing. 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 DNA-binding of TRα and canonical TRα signaling (TRαGS). Cardiac function was assessed by echocardiography, remodeling was assessed by histological staining (H&E and SR). TH levels in serum were analyzed by ELISA. Further, sarcomere contraction parameters as well as cardiomyocyte hypertrophy were analyzed using isolated adult cardiomyocytes (CM) from WT, TRαKO and TRαGS mice or neonatal mouse CM (NMCM), respectively. Cardiac vascularization was determined by ani-CD31 immunohistochemistry.

Results: Eight weeks after LAD ligation, heart weight and histologically determined CM size were increased in T3 (500 ng/ml) treated WT mice compared to solvent treated controls. Echocardiography and histological analyses revealed a significantly improved ejection fraction, reduced fibrosis within the remote area and a reduced infarct size in response to T3. Interestingly, the total cardiac vessel number increased with T3 dose and proportional to heart weight, indicating T3-induced neoangiogenesis. Comparison of untreated WT, TRαKO and TRαGS hearts suggests that this effect originates from noncanonical TRα signaling as TRαGS mice had the highest total cardiac vessel length among the genotypes. In vitro analyses using CM isolated from WT, TRαKO and TRαGS hearts suggest significant differences in contractility shown by reduced maximal sarcomere shortening of TRαKO and TRαGS compared to WT. Similarly, as observed in vivo, we could successfully induce hypertrophic growth of NMCM by 48 h T3 treatment.

Conclusion/Outlook: Our experiments show that T3 is indeed cardioprotective in IHD with improved cardiac function and vascularization eight weeks after myocardial infarction. Current experiments will reveal further how canonical and noncanonical TRα signaling is involved in these T3 mediated cardioprotective effects.