SENP1 Protects Against Pressure Overload‐Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling

Abstract

Background SENP1 (sentrin/small ubiquitin‐like modifier‐specific protease 1) has emerged as a significant modulator involved in the pathogenesis of a variety of human diseases, especially cancer. However, the regulatory roles of SENP1 in cardiovascular biology and diseases remain controversial. Our current study aims to clarify the function and regulation of SENP1 in pressure overload‐induced cardiac remodeling and dysfunction. Methods and Results We used a preclinical mouse model of transverse aortic constriction coupled with in vitro studies in neonatal rat cardiomyocytes to study the role of SENP1 in cardiac hypertrophy. Gene delivery system was used to knockdown or overexpress SENP1 in vivo. Here, we observed that SENP1 expression was significantly augmented in murine hearts following transverse aortic constriction as well as neonatal rat cardiomyocytes treated with phenylephrine or angiotensin II. Cardiac‐specific SENP1 knockdown markedly exacerbated transverse aortic constriction‐induced cardiac hypertrophy, systolic dysfunction, fibrotic response, and cellular apoptosis. In contrast, adenovirus‐mediated SENP1 overexpression in murine myocardium significantly attenuated cardiac remodeling and dysfunction following chronic pressure overload. Mechanistically, JAK2 (Janus kinase 2) and STAT3 (signal transducer and activator of transcription 3) acted as new interacting partners of SENP1 in this process. SENP1‐JAK2/STAT3 interaction suppressed STAT3 nuclear translocation and activation, ultimately inhibiting the transcription of prohypertrophic genes and the initiation of hypertrophic response. Furthermore, cardiomyocyte‐specific STAT3 knockout mice were generated to validate the underlying mechanisms, and the results showed that STAT3 ablation blunted the cardiac hypertrophy‐promoting effects of SENP1 deficiency. Additionally, pharmacological inhibition of SENP1 by Momordin Ic amplified cardiac remodeling post‐transverse aortic constriction. Conclusions Our study provided evidence that SENP1 protected against pressure overload‐induced cardiac remodeling and dysfunction via inhibiting STAT3 signaling. SENP1 supplementation might constitute a new promising treatment against cardiac hypertrophy. Notably, cardiovascular side effects should be seriously considered while applying systemic SENP1 blockers to suppress tumors.

SUMOylation of TEAD1 Modulates the Mechanism of Pathological Cardiac Hypertrophy

“…Recent studies have elucidated the role of SENP1 in cardiac hypertrophy. [ 26 ] The expression of SENP1 is dysregulated in hypertrophic hearts, exerting a profound effect on cardiac remodeling. [ 27 ] To determine whether the expression of SENP1 is associated with cardiac hypertrophy, we measured the mRNA and protein expression levels of SENP1 in a TAC surgery‐induced hypertrophic mouse model and in NRCMs treated with Ang II.…”

Leucine zipper protein 1 prevents doxorubicin-induced cardiotoxicity in mice

“…To generate cardiac-specific Luzp1 knockout (cKO) mice, Luzp1 floxed mice mated with the α-Mhc -MerCreMer transgenic mice (C57BL/6J background; stock no. 005650, the Jackson Laboratory) as we previously described [ 19 , 20 ]. To induce the deletion of Luzp1 in cardiomyocytes, LUZP1 cKO mice were intraperitoneally injected with 25 mg/kg tamoxifen daily for 5 successive days.…”

Cardiomyocytes Deficiency of SENP1 Promotes Myocardial Fibrosis via Paracrine Action

“…A recent study demonstrated that gene delivery system-mediated knockdown of SENP1 exacerbates pressure overload-induced myocardial hypertrophy and interstitial fibrosis, accelerating the progression of heart failure. 10 Additionally, heterozygous SENP1 knockout aggravated myocardial ischemia/reperfusion (I/R) injury by inhibiting the expression of hypoxia-inducible factor 1α (HIF1α). 11 These results suggest that SENP1 is an important candidate gene for the treatment of cardiovascular disease.…”