Circ-SIRT1 inhibits cardiac hypertrophy via activating SIRT1 to promote autophagy

Weichen Wang,Longlong Wang,Mengyue Yang,Chunwei Wu,Rui Lan,Yuze Li,Weiwei Wang

doi:10.1038/s41419-021-04059-y

Weichen Wang, Longlong Wang + Show 5 more

Open Access

https://doi.org/10.1038/s41419-021-04059-y

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Abstract

Mounting studies have substantiated that abrogating autophagy contributes to cardiac hypertrophy (CH). Sirtuin 1 (SIRT1) has been reported to support autophagy and inhibit CH. However, the upstream regulation mechanism behind the regulation of SIRT1 level in CH remains unclear. Circular RNAs (circRNAs) are vital modulators in diverse human diseases including CH. This study intended to investigate the regulatory mechanism of circRNA on SIRT1 expression in CH. CH model was established by angiotensin II (Ang II) fusion or transverse aortic constriction (TAC) surgery and Ang II treatment on hiPSC-CMs and H9c2 cells in vitro. Our results showed that circ-SIRT1 (hsa_circ_0093884) expression was downregulated in Ang II-treated hiPSC-CMs, and confirmed that its conserved mouse homolog circ-Sirt1 (mmu_circ_0002354) was expressed at low levels in Ang II-treated H9c2 cells and TAC-induced mice model. Functionally, circ-SIRT1/circ-Sirt1 attenuated Ang II-induced CH and induced autophagy in hiPSC-CMs and H9c2 cardiomyocytes. Mechanistically, circ-SIRT1 could upregulate its host gene SIRT1 at the post-transcriptional level by sponging miR-3681-3p/miR-5195-3p and stabilized SIRT1 protein at the post-translational level by recruiting USP22 to induce deubiquitination on SIRT1 protein. Further, SIRT1 knockdown could rescue the effect of circ-SIRT1 upregulation on Ang II-induced CH and autophagy in vitro and in vivo. In conclusion, we first uncovered that circ-SIRT1 restrains CH via activating SIRT1 to promote autophagy, indicating circ-SIRT1 as a promising target to alleviate CH.

Highlights

Cardiac hypertrophy (CH), featuring enlarged cardiomyocytes as well as heart mass, is generally depicted as a significant compensatory mechanism of the heart in response to diverse physiological and pathological overloads, and it helps sustain cardiac function in its original stage [1, 2]
Sirtuin 1 (SIRT1) is one of the histone deacetylases (HDACs) that bind to protein lysine residues to trigger de-acetylation [42]
Regulation of SIRT1 by circRNAs has been elucidated in some cancers and diseases [25, 27, 44], our study was the first to uncover the circRNA-mediated regulation of SIRT1 in CH

Summary

Introduction

Cardiac hypertrophy (CH), featuring enlarged cardiomyocytes as well as heart mass, is generally depicted as a significant compensatory mechanism of the heart in response to diverse physiological and pathological overloads, and it helps sustain cardiac function in its original stage [1, 2]. Pathological CH is a common risk factor for heart failure and multiple factors contributed to CH, including aging and neurohumoral activation (e.g., Ang II) [6]. Antiaging approaches, such as the restriction of caloric, can benefit cardiac functions in rodents, monkeys as well as human beings [7,8,9]. To improve the quality of CH treatment and prevent ultimate heart failure, it is of considerable significance to identify potent therapeutic targets that may modulate CH

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