Myofibroblast-specific inhibition of ASPP1 alleviates myocardial fibrosis by enhancing p53 degradation

Abstract

Abstract In the healing process of myocardial infarction, cardiac fibroblasts are activated and serious cardiac fibrosis developed, which eventually leads to cardiac remodeling and heart failure. Our recent study showed that ASPP1 (apoptosis stimulating of p53 protein 1) promotes cardiomyocyte apoptosis by enhancing nuclear trafficking of p53. As p53 is a key regulator of cardiac fibroblast activation, we thus explored the influence of ASPP1 on myocardial fibrosis and the molecular mechanisms related to p53.Here, we observed ASPP1 was increased after 4 weeks of myocardial infarction (MI). Both global and myofibroblast-specific knockout of ASPP1 in mice mitigated cardiac dysfunction, fibrosis and remodeling after MI. Strikingly, ASPP1 produced opposite influence on p53 level and cell fate of cardiac fibroblast than cardiomyocytes. Knockdown of ASPP1 increased p53 level and inhibited the activity of cardiac fibroblasts. The immunofluorescent staining revealed that upon TGF-b1 stimulation ASPP1 accumulates in the cytoplasm of fibroblasts while the level of p53 was reduced, and inhibition of ASPP1 increased p53 level and promoted p53 nuclear translocation. Mechanistically, ASPP1 directly binds to deubiquitinase OTUB1 and prevents its binding with p53, thereby promoting the ubiquitination and degradation of p53. Targeting ASPP1 may be a promising strategy for the treatment of myocardial fibrosis.