The Emerging Role of TRα1 in Cardiac Repair: Potential Therapeutic Implications

Abstract

Thyroid hormone (TH) is critical for adapting living organisms to environmental stress. Plasma circulating tri-iodothyronine (T3) levels drop in most disease states and are associated with increased oxidative stress. In this context, T3 levels in plasma appear to be an independent determinant for the recovery of cardiac function after myocardial infarction in patients. Thyroid hormone receptor α1 (TRα1) seems to be crucial in this response; TRα1 accumulates to cell nucleus upon activation of stress induced growth kinase signaling. Furthermore, overexpression of nuclear TRα1 in cardiomyocytes can result in pathological or physiological growth (dual action) in absence or presence of its ligand, respectively. Accordingly, inactivation of TRα1 receptor prevents reactive hypertrophy after myocardial infarction and results in heart failure with increased phospholamban (PLB) expression and marked activation of p38MAPK. In line with this evidence, TH is shown to limit ischemia/reperfusion injury and convert pathologic to physiologic growth after myocardial infarction via TRα1 receptor. TRα1 receptor may prove to be a novel pharmacological target for cardiac repair/regeneration therapies.

Hypothyroidism modifies morphometry and thyroid‐hormone receptor expression in periurethral muscles of female rabbits

“…Moreover, it is possible that the augmentation in the anti‐TRα positive myonuclei of the Bsm could be related to the polymyositis observed in this muscle. The fact that the TRα is involved in inflammatory and regeneration processes in cardiac striated fibers and the liver, supports this proposal …”

The impact of thyroid hormone dysfunction on ischemic heart disease

“…Some factors may predict a more pronounced decline in T3 levels, such as worsening angina pectoris preceding acute myocardial infarction, known chronic heart failure or previous myocardial infarction and diabetes mellitus (89). Low T3 levels also induce oxidative stress and increase apoptotic rate, which may worsen ventricular dysfunction (90). Therefore, THs levels are an important factor modulating left ventricular structure, function and geometry during the late post-myocardial infarction period (91).…”

Restoration of thyroid hormone balance: a game changer in the treatment of heart failure?

“…TH signaling is complex and becoming more so as new information arises. Since there are many compre-hensive reviews on the topic (8,32,82,91,97), it will be discussed only briefly here. THs signal genomically through nuclear TRs.…”

“…Animal and human studies have generally shown downrgulation of TRs in hypertrophy and HF, suggesting another mechanism by which TH function may be reduced even when serum hormone levels are normal (62,63,100). Nonetheless, there is considerable controversy in this area of research, particularly with regard to results from gene-targeted mouse studies that may represent more extreme changes than those typically occuring in real life (97). Impaired TR␣ signaling, in particular, likely plays a major role in cardiac dysfunction and adverse remodeling in heart diseases (88,98).…”

“…A clinical study (78) has also shown that improved early and late functional recovery after MI tracks with improved serum T 3 levels but not with T 4 . Importantly, TR␣, the major TR in the heart regulating sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA) and myosin isoform expression, is highly regulated by T 3 (97). Nonetheless, animal and clinical studies have shown cardiac benefits from either T3 or T 4 treatment.…”