Acute, high dose triiodothyronine prevents tissue hypothyroidism and improves cardiac remodelling in a rat model of myocardial ischemia/reperfusion
P Mantzouratou, E Malaxianaki, A Katsaouni, I Kalifatidis, A M Lavecchia, E Mouchtouri, T Lamprou, M Mavroidis, C Xinaris, C Pantos, I MourouzisAbstract
Abstract
Introduction: Acute myocardial infarction (AMI) remains a leading cause of heart failure, necessitating the development of novel therapeutic approaches. Thyroid hormone (ΤΗ) signalling is recognized for its role in post-AMI cardiac remodelling, and numerous preclinical studies highlight its therapeutic potential. A phase II clinical trial (Thy-Repair) showed that acute, high dose triiodothyronine (T3) in patients with anterior AMI prevents long-term cardiac remodelling.
Purpose
This study investigated the molecular basis of the beneficial effects of acute, high-dose T3 treatment using a rat model of ischaemia/reperfusion (IR) mimicking the design of the clinical trial Thy-Repair.
Methods
Wistar rats were subjected to IR and randomly assigned to receive either T3 (20μg/Kg) or vehicle treatment intraperitoneally. Treatment started immediately after opening of the left coronary artery ligation and repeated after 24 hours. Myocardial samples were studied at 3, 7 and 14 days after AMI.
Results
T3 treatment ameliorated cardiac structure and function, as assessed by echocardiography. Histological analysis demonstrated reduced myocardial injury, fibrosis and inflammatory cell infiltration, along with the induction of physiological hypertrophy. At the molecular level, T3 increased the expression of survival signalling pathways, including Akt and AMPK, while decreasing ERK activation. Importantly, T3 prevented the expression of deiodinase 3 (DIO3), which locally inactivates T3, thereby rescuing the heart from tissue hypothyroidism.
Conclusion
Acute, high dose T3 treatment prevents tissue hypothyroidism by reducing DIO3 expression and modulates key intracellular signalling pathways, contributing to improved post-ischaemic cardiac remodelling.