New insights into thyroid hormone (TH) action in ischemic heart disease

Stefanie Dörr (Dortmund)1, S. Grund (Essen)2, S. Hönes (Essen)2, D. Führer (Essen)2, L. Möller (Essen)2, K. Lorenz (Würzburg)3

1Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V. Kardiovaskuläre Pharmakologie Dortmund, Deutschland; 2Universitätsklinikum Essen Klinik für Endokrinologie, Diabetologie und Stoffwechsel Essen, Deutschland; 3Universitätsklinikum Würzburg Institut für Pharmakologie und Toxikologie Würzburg, Deutschland


Background: Ischemic heart disease (IHD) is one of the leading causes of mortality worldwide, underlining the necessity to identify novel therapeutic approaches. Thyroid hormones (TH), including T3 and T4 have a significant effect on cardiac function and may even improve outcome following acute ischemia/reperfusion and in chronic heart failure. However, the TH signaling mechanism within the heart remains incompletely understood.

Aim: This study seeks to explore the impact of TH receptor alpha (TRα) on IHD on the heart and ventricular remodeling by utilizing mouse models. These models allow the evaluation of both canonical and non-canonical TH signaling, which involve DNA-binding and gene expression regulation or cytosolic signaling pathway activation, respectively.

Materials & Methods: 8-10-week-old C57BL/6J mice underwent permanent ligation of the left descending coronary artery (LAD). They were administered and were treated p.o. with 500 ng/ml T3 for 8 weeks right following surgery. To investigate the effect of various TH signaling pathways, we included wild-type (WT) mice, TR alpha knockout (TRαKO) mice, and knock-in mice with a TR alpha mutation that eliminates DNA binding and canonical TR alpha signal (TRαGS). Cardiac remodeling was assessed by histological staining (H&E and SR). Serum TH levels were analyzed using ELISA. Additionally, sarcomere contraction parameters of and cardiomyocyte hypertrophy were examined by using isolated adult cardiomyocytes (CM) from WT, TRαKO and TRαGS mice or neonatal mouse CM (NMCM), respectively. Cardiac vascularization was assessed by anti-CD31 immunohistochemistry.

Results: Eight weeks after LAD ligation, wild type mice treated with T3 (500 ng/ml) exhibited an increased heart weight and cardiac myocyte size compared to solvent-treated controls. Histological analyses demonstrated less fibrosis in the remote area and a decreased infarct size in response to T3. Interestingly, the total number of cardiac vessels increased with T3 dosage and in proportion to heart weight, suggesting T3-induced neoangiogenesis. The comparison of untreated wild-type (WT), TRα knockout (TRαKO) and TRα knock-in mutant (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 hearts of WT, TRαKO and TRαGS mice indicate noteworthy differences in contractility, demonstrating reduced maximal sarcomere shortening of TRαKO and TRαGS compared to WT. Additionally, after 48 hours of T3 treatment, we observed successful stimulation of hypertrophic growth in neonatal mouse cardiomyocytes (NMCM), similarly as observed in vivo.

Conclusion/Outlook: In conclusion, our experiments demonstrate that T3 offers cardioprotective benefits in IHD by reducing infarct size and increasing vascularization eight weeks post-myocardial infarction. Further investigations will determine the extent of involvement of canonical and noncanonical TRα signaling in the cardioprotective effects mediated by T3.

Diese Seite teilen