Figure 3.

Possible mechanism of MED13-mediated regulation of cardiac function in response to hypothyroidism. Top panel: The T3 induces α-MHC gene transcription through TR binding a positive TRE and inhibits β-MHC transcription via TR binding a negative TRE. The intron in the α-MHC gene encodes miR-208a. In the context of hypothyroidism (PTU inhibits T4 synthesis and suppresses conversion from T4 to T3), miR-208a may inhibit cardiac MED13 and additional targets expression, which regulates TH receptor activity and β-MHC gene expression. T3 also enhances expression of Serca2a via TR binding TREs in its regulatory region. Changes in the level of α/β-MHC and Serca2a expression could affect cardiac function in the context of hypothyroidism. Lower panel: Cardiac contractility function is suppressed by PTU. Overexpression of cardiac MED13 ameliorates cardiac dysfunction induced by hypothyroidism, whereas deletion of cardiac MED13 aggravates hypothyroidism-related cardiac dysfunction. The expression of serca2a and myh7 are lower in the hearts of MED13-cKO mice than wild-type mice treated with PTU and pro-inflammatory/pro-fibrotic genes expression are higher in MED13-cKO mice. These changes are associated with worse cardiac dysfunction in MED13-cKO mice than in wild-type mice. (PTU, propylthiouracil; T4, thyroxine; T3, triiodothyronine; TR, thryoid hormone receptor; TRE, thyroid hormone response element).