Beta‐arrestin 2 mediates cardiac hypertrophy induced by thyroid hormones via AT1R

Abstract

We have previously reported that angiotensin II receptor type 1 (AT1R) contributes to the hypertrophic effects of thyroid hormones (TH) in cardiac cells. Even though evidence indicates crosstalks between TH and AT1R, the underlying mechanisms are poorly understood. Beta-arrestin (ARRB) signaling has been described as noncanonical signal transduction pathway that exerts important effects in the cardiovascular system through G-protein-coupled receptors, as AT1R. Herein, we investigated the contribution of ARRB signaling in TH-induced cardiomyocyte hypertrophy. Primary cardiomyocyte cultures were treated with Triiodothyronine (T3) to induce cell hypertrophy. T3 rapidly activates extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, which was partially inhibited by AT1R blockade. Also, ERK1/2 inhibition attenuated the hypertrophic effects of T3. ARRB2 was upregulated by T3, and small interfering RNA assays revealed the role of ARRB2-but not ARRB1-on ERK1/2 activation and cardiomyocyte hypertrophy. Corroborating these findings, the ARRB2-overexpressed cells showed increased expression of hypertrophic markers, which were attenuated by ERK1/2 inhibition. Immunocytochemistry and immunoprecipitation assays revealed the increased expression of nuclear AT1R after T3 stimulation and the increased interaction of AT1R/ARRB2. The inhibition of endocytosis also attenuated the T3 effects on cardiac cells. Our results evidence the contribution of ARRB2 on ERK1/2 activation and cardiomyocyte hypertrophy induced by T3 via AT1R.

Insights Into the Role of Angiotensin-II AT 1 Receptor-Dependent β-Arrestin Signaling in Cardiovascular Disease

“…Recently, it was reported that increased thyroid hormone activity is associated with AT 1 R-dependent cardiac hypertrophy. 49 The underlying mechanism suggests that β-arrestin-induced ERK signaling induced the hypertrophic effect as small interfering RNA-mediated ablation of β-arrestin-2 alleviated cardiac hypertrophy. Additionally, it has been noted that cardiac remodeling due to chronic Ang II exposure is mediated by the recruitment and internalization of β-arrestin-1 and L-type calcium channel, leading to a decrease in Ca 2+ flux.…”