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

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.

The sirtuin family in health and disease

“… 4 Some in vivo studies have suggested that SIRT1 overexpression can alleviate Ang II-induced cardiac hypertrophy by reducing cardiomyocyte apoptosis and promoting autophagy. 498 , 499 In addition, SIRT1 overexpression can ameliorate cardiac hypertrophy induced by phenylephrine by inhibiting protein kinase C (PKC)‐ζ activation. 500 However, some studies have shown the opposite effect.…”

Activation of FMS ‐like tyrosine kinase 3 protects against isoprenaline‐induced cardiac hypertrophy by improving autophagy and mitochondrial dynamics

“…Ma et al also described that USP22 protects against myocardial ischemia–reperfusion injury via the stabilization of SIRT1 51 . Similarly, Wang et al demonstrated that USP22‐induced deubiquitination of SIRT1 inhibits Angiotensin II or transverse aortic constriction induced cardiac hypertrophy 52 . In the present work, we identified that activation of Flt3 is capable of upregulating SIRT1 protein expression in vivo and in vitro, but we are not sure whether the activation of Flt3 induces expression of USP22 in the setting of our current work, thus leading to deubiquitination of SIRT1 and its upregulation, so more work is needed.…”

Identification of circular RNAs in cardiac hypertrophy and cardiac fibrosis

“…Specifically, in their study, ceRNA network play an important role in pathogenesis of cardiac hypertrophy. Circ-SIRT1 bound with miR-3681-3p and miR-5195-3p to regulate SIRT1 expression post-transcriptionally ( Wang et al, 2021 ). In another study, Wu et al indicated that circ Yap is a critical regulator in cardiac fibrosis in the pressure overload mouse model ( Wu et al, 2021 ).…”