Reduced expression of thyroid hormone receptors and beta-adrenergic receptors in human failing cardiomyocytes

Abstract

An altered thyroid hormone profile has been reported in patients with congestive heart failure. However, information regarding the status of thyroid hormone receptors in human failing cardiomyocytes is lacking. Therefore the expression of thyroid hormone and beta-adrenergic receptors was investigated in human ventricular cardiomyocytes isolated from patients with end-stage heart failure (FM, n=12), or from tentative donors (C, n=4). The expression of thyroid (TRalpha1, and TRbeta1) and beta-adrenergic receptors (ARB1 and ARB2) was measured at both the gene, and at the protein level. In FM the reduced mRNA expression of ARB1 (p<0.05, -37%) and ARB2 (p<0.05, -42%) was associated with a reduction of the messenger for TRalpha1 (p<0.05, -85%) and TRalpha2 (p<0.05, -73%). These findings were confirmed at the protein level for ARB1, ARB2 and TRalpha1. These data reveal that in human heart failure the reduction of beta-adrenergic receptors is associated with reduced expression of both TRalpha1 and TRalpha2 isoforms of thyroid hormone receptors

Thyroid and Cardiovascular Disease: Research Agenda for Enhancing Knowledge, Prevention, and Treatment

“…Restoration of TR levels by adeno-associated virus (AAV) transgene expression significantly improves cardiac contractile function (124). In humans, a decrease in TRa1 has been reported in patients with cardiomyopathies (125).…”

Sex-related differences in age-associated downregulation of human ventricular myocardial β1-adrenergic receptors

“…Possibilities include sex differences in cardiac adrenergic activity with age, the effects of sex hormones directly or through an interaction with adrenergic activity, 39 thyroid hormone effects, 12 or differential regulation by microRNAs. 40 In addition to being a biosensor of cardiac adrenergic activity, the decline in β 1 -AR density may be an adaptive change that protects the heart from adverse adrenergic signaling.…”

“…3 Inhibition of this gene network likely explains much of the clinical benefit of β-blocking agents in chronic heart failure with reduced ejection fraction (HFrEF). 3,5,6 Major influences on β 1 -AR expression in human ventricular myocardium include age, 7,8 chronic administration of β-agonists 9 or antagonists, 10 thyroid hormone, 11,12 and HFrEF, 2,13 the latter likely through locally regulated chronic increases in adrenergic activity. 14 Modulators of β 1 -AR function independent of protein expression include the ADRB1 Arg389Gly genotype 15,16 and acute exposure to adrenergic stimulation.…”

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

“…TR α 1 protein expression was measured in subsequent studies in cardiac specimens from patients with heart failure. TR α 1 was found to be upregulated in one study [44] and downregulated in another study [45]. To add to the controversy, TR α 1 was shown to be overexpressed [46] or downregulated [47] in animal models of cardiac remodeling after myocardial infarction.…”