SENP1 Protects Against Pressure Overload-Induced Cardiac Remodeling and Dysfunction Via Inhibiting STAT3 Signaling.
Dan YangDi FanZhen GuoFang-Yuan LiuMing-Yu WangPeng AnZheng YangQi-Zhu TangPublished in: Journal of the American Heart Association (2022)
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.
Keyphrases
- left ventricular
- oxidative stress
- high glucose
- angiotensin ii
- cell proliferation
- diabetic rats
- aortic valve
- mouse model
- endothelial cells
- magnetic resonance imaging
- heart failure
- transcription factor
- signaling pathway
- blood pressure
- poor prognosis
- neuropathic pain
- drug induced
- genome wide
- squamous cell carcinoma
- gene expression
- stem cells
- immune response
- copy number
- dna methylation
- computed tomography
- angiotensin converting enzyme
- nuclear factor
- vascular smooth muscle cells
- hiv infected
- aortic dissection
- pulmonary arterial hypertension
- spinal cord
- induced pluripotent stem cells
- contrast enhanced
- replacement therapy
- genome wide identification