Targeting WWP1 ameliorates cardiac ischemic injury by suppressing KLF15-ubiquitination mediated myocardial inflammation

Abstract

Rationale: Previous studies have suggested that myocardial inflammation plays a critical role after ischemic myocardial infarction (MI); however, the underlying mechanisms still need to be fully elucidated. WW domain-containing ubiquitin E3 ligase 1 (WWP1) is considered as an important therapeutic target for cardiovascular diseases due to its crucial function in non-ischemic cardiomyopathy, though it remains unknown whether targeting WWP1 can alleviate myocardial inflammation and ischemic injury post-MI. Methods: Recombinant adeno-associated virus 9 (rAAV9)-cTnT-mediated WWP1 or Kruppel-like factor 15 (KLF15) gene transfer and a natural WWP1 inhibitor Indole-3-carbinol (I3C) were used to determine the WWP1 function in cardiomyocytes. Cardiac function, tissue injury, myocardial inflammation, and signaling changes in the left ventricular tissues were analyzed after MI. The mechanisms underlying WWP1 regulation of cardiomyocyte phenotypes in vitro were determined using the adenovirus system. Results: We found that WWP1 expression was up-regulated in cardiomyocytes located in the infarct border at the early phase of MI and in hypoxia-treated neonatal rat cardiac myocytes (NRCMs). Cardiomyocyte-specific WWP1 overexpression augmented cardiomyocyte apoptosis, increased infarct size and deteriorated cardiac function. In contrast, inhibition of WWP1 in cardiomyocytes mitigated MI-induced cardiac ischemic injury. Mechanistically, WWP1 triggered excessive cardiomyocyte inflammation after MI by targeting KLF15 to catalyze K48-linked polyubiquitination and degradation. Ultimately, WWP1-mediated degradation of KLF15 contributed to the up-regulation of p65 acetylation, and activated the inflammatory signaling of MAPK in ischemic myocardium and hypoxia-treated cardiomyocytes. Thus, targeting of WWP1 by I3C protected against cardiac dysfunction and remodeling after MI. Conclusions: Our study provides new insights into the previously unrecognized role of WWP1 in cardiomyocyte inflammation and progression of ischemic injury induced by MI. Our findings afford new therapeutic options for patients with ischemic cardiomyopathy.

FBXL8 inhibits post-myocardial infarction cardiac fibrosis by targeting Snail1 for ubiquitin-proteasome degradation

“…Cumulative studies have demonstrated that the SCF E3 ubiquitin ligase family acts as an important regulator of post-translational modification and is closely associated with cardiovascular diseases such as cardiac hypertrophy, myocardial infarction, arrhythmia, and myocardiotoxicity [ 26 , 27 ]. For example, FBXL22 was identified as a cardiac-enriched F-box protein that modulates sarcomeric protein turnover and is critical for maintaining contractile function in vivo [ 28 ].…”

Effect of miR-182-5p on apoptosis in myocardial infarction

“…Numerous studies connect ischemic cardiomyopathy and specific congenital heart diseases to cell apoptosis [ 17 , 20 , 21 ]. The consequences of ischemia- and hypoxia-induced myocardial cell apoptosis are severe, leading to adverse cardiac outcomes such as ventricular remodeling [ 11 , 22 , 23 ]. The exact role of miR-182-5p in these apoptosis pathways remains ambiguous.…”

Krüpple-like factors in cardiomyopathy: emerging player and therapeutic opportunities

“…It has been reported that KLF15 is an upstream regulator of metabolic gene expression, and that it is negatively regulated by EZH2 (an epigenetic regulator) in a SET structural domain-dependent manner for cardiac metabolism and structural reprogramming ( 92 ). Additionally, KLF15 suppresses gene expression and negatively regulates adverse cardiac remodeling and hypertrophy in ICM progression ( 72 , 92 , 96 ). Specifically, KLF15 antagonizes the expression of various genes actively involved in cardiac remodeling.…”