Knockdown of endogenous RNF4 exacerbates ischaemia‐induced cardiomyocyte apoptosis in mice

Abstract

RNF4, a poly‐SUMO‐specific E3 ubiquitin ligase, is associated with protein degradation, DNA damage repair and tumour progression. However, the effect of RNF4 in cardiomyocytes remains to be explored. Here, we identified the alteration of RNF4 from ischaemic hearts and oxidative stress‐induced apoptotic cardiomyocytes. Upon myocardial infarction (MI) or H2O2/ATO treatment, RNF4 increased rapidly and then decreased gradually. PML SUMOylation and PML nuclear body (PML‐NB) formation first enhanced and then degraded upon oxidative stress. Reactive oxygen species (ROS) inhibitor was able to attenuate the elevation of RNF4 expression and PML SUMOylation. PML overexpression and RNF4 knockdown by small interfering RNA (siRNA) enhanced PML SUMOylation, promoted p53 recruitment and activation and exacerbated H2O2/ATO‐induced cardiomyocyte apoptosis which could be partially reversed by knockdown of p53. In vivo, knockdown of endogenous RNF4 via in vivo adeno‐associated virus infection deteriorated post‐MI structure remodelling including more extensive interstitial fibrosis and severely fractured and disordered structure. Furthermore, knockdown of RNF4 worsened ischaemia‐induced cardiac dysfunction of MI models. Our results reveal a novel myocardial apoptosis regulation model that is composed of RNF4, PML and p53. The modulation of these proteins may provide a new approach to tackling cardiac ischaemia.

SUMO-specific Isopeptidases Tuning Cardiac SUMOylation in Health and Disease

“…As discussed above, RNF4 has been implicated in the degradation of PML, a scaffold for multiprotein complex nuclear bodies. Here, knockdown of endogenous RNF4 in adult murine hearts exacerbated oxidative stress-induced cardiomyocyte apoptosis and ischaemia-induced cardiac dysfunction, which was associated with enhanced PML nuclear bodies accumulation, p53 recruitment and activation (Figure 3) (Qiu et al, 2020). We propose that SENP6 and SENP7, by counteracting RNF4 action on PML and, possibly other targets might also interplay in the complex regulatory landscape of ischemic adaptation.…”

“…Unfortunately, less is known about the role of SENP6 or SENP7 in cardiac I/R injury. However, an interesting new aspect emerges based on a recent study (Qiu et al, 2020) regarding the role of RNF4 that targets poly-SUMO-modified proteins for ubiquitin-mediated proteolysis (Plechanovová et al, 2011). As discussed above, RNF4 has been implicated in the degradation of PML, a scaffold for multiprotein complex nuclear bodies.…”

The Function of SUMOylation and Its Critical Roles in Cardiovascular Diseases and Potential Clinical Implications

“…PML is an ROS sensor, and myocardial infarction (MI) generated ROS, and ROS induced the increase of PML SUMOylation and PML-NB formation, leading to p53-dependent cell apoptosis. Overexpression of PML or knockdown of RNF4 enhances p53 recruitment and activation of PML SUMOylation and PML NBs accumulation, which aggravated ischemia-induced cardiomyocyte apoptosis in vivo and cell injury [ 84 ]. These results indicated the important roles of PML SUMOylation in ischemia and suggested that intervening in the dynamic pattern of PML SUMOylation under oxidative stress is a potential treatment of MI.…”

“…PML SUMOylation is critical in PML NBs formation [83] and aggravates ischemia-induced cardiomyocyte apoptosis in vivo [84].…”

SUMOylation as a Therapeutic Target for Myocardial Infarction

“…This review aims to update the current knowledge on the role of SUMOylation and SUMOylated proteins in the pathology and cardiac repair of MI. Previous studies have reported some SUMOylation proteins as targets for the treatment of MI (15)(16)(17). Thus, this review discussed the effects of the SUMOylation on the subcellular location of these protein targets and the progression of MI and overview the functions and clinical application stages of protein SUMOylation.…”