Review Article

New Insights into Mechanisms of Cardioprotection Mediated by Thyroid Hormones

Figure 1

Schematic representation of cardioprotective mechanisms of T3. Coloured details refer to emerging findings, and established mechanisms are depicted in gray scale. Top left: antifibrotic effect on CF. T3 binding to TRβ/α represses AP-1 activity resulting in MMP1 downregulation. Moreover T3 inhibits collagen synthesis through the classical genomic pathway mediated by TRβ1. The upregulation of the antifibrotic miRNA-29 by T3 opens a new window of investigation. Bottom left: proangiogenic and vasorelaxing effects of T3 on VS. T3 stimulates EC proliferation through the interaction with a plasma membrane integrin receptor. Signal transduction is mediated by activation of ERK1/2 and results in downstream transcription of proangiogenic genes such as VEGF and bFGF. The interaction of T3 with cytoplasmic TRβ1 activates PI3K/AKT. The signal cascade leads to stimulation of Hif1-α with consequent increase of EC proliferation and vessel collateraization. In smooth muscle cells T3-mediated reduction of vascular tone is achieved by stimulation NOS activity and by the recently reported upregulation of K+ch. Top right: antiapoptotic and antinecrotic effects on CM. Classical genomic action of T3 increases PGC1-α expression which in turn up-regulates mtTFA; the resulting increase of mitochondrial biogenesis and function improves cell viability. As recently reported, T3 might limit mitochondrial-mediated apoptosis and necrosis by reducing mitochondrial matrix calcium overload and by favouring the opening of the cardioprotective mitoK-ATP channel. Upregulation of the antiapoptotic miRNA-30a pathway by T3 represents an emerging finding that encourages future researches. Right bottom: inhibition of CM pathological hypertrophy. Through the classical genomic mechanism, T3 regulates the expression of several genes critically involved in contractile function such as α/β-MHC, SERCA2, Na/K-ATPase, PLB, and Na/Ca exchanger. Another way of T3-mediated upregulation of protein expression requires the activation of the PI3K/AKT/mTOR axes. Histone modifications of MHC gene have been involved in T3-mediated regulation of MHC isoform composition. T3 can also affect myocardial MHC expression through regulation of a family of miRNAs (miRNA-208a, miRNA-208b, and miRNA-499) encoded by MHC genes.
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