Cardioprotection by Hypothyroidism Is Not Mediated by Favorable Hemodynamics-Role of Canonical Thyroid Hormone Receptor Alpha Signaling

Hypothyroidism has been shown to reduce infarct size in rats, but the underlying mechanisms are unclear. We used isolated pressure-constant perfused hearts of control, hypothyroid and hyperthyroid mice and measured infarct size, functional parameters and phosphorylation of key molecules in cardioprotective signaling with matched heart rate. Compared with controls, hypothyroidism was cardioprotective, while hyperthyroidism was detrimental with enlarged infarct size. Next, we asked how thyroid hormone receptor alpha (TR alpha) affects ischemia/reperfusion (IR) injury. Thus, canonical and noncanonical TR alpha signaling was investigated in the hearts of (i) mice lacking TR alpha (TR alpha(0)), (ii) with a mutation in TR alpha DNA-binding domain (TR alpha(GS)) and (iii) in hyperthyroid TR alpha(0) (TR alpha(0)hyper) and TR alpha(GS) mice (TR alpha(GS)hyper). TR alpha(0) mouse hearts were protected against IR injury. Furthermore, infarct size was reduced in the hearts of TR alpha(GS) mice that lack canonical TR alpha signaling but maintain noncanonical TR alpha action. Hyperthyroidism did not increase infarct size in TR alpha(0) and TR alpha(GS) mouse hearts. These cardioprotective effects were not associated with increased phosphorylation of key proteins of RISK, SAFE and eNOS pathways. In summary, chronic hypothyroidism and the lack of canonical TR alpha signaling are cardioprotective in IR injury and protection is not due to favorable changes in hemodynamics.

Automated summary

Hypothyroidism and the lack of canonical TR alpha signaling have been shown to be cardioprotective in ischemia/reperfusion injury by reducing infarct size.