iASPP protects the heart from ischemia injury by inhibiting p53 expression and cardiomyocyte apoptosis

Abstract

Currently, there remains a great need to elucidate the molecular mechanism of acute myocardial infarction in order to facilitate the development of novel therapy. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is a member of the ASPP family proteins and an evolutionarily preserved inhibitor of p53 that is involved in many cellular processes, including apoptosis of cancer cells. The purpose of this study was to investigate the possible role of iASPP in acute myocardial infarction. The protein level of iASPP was markedly reduced in the ischemic hearts in vivo and hydrogen peroxide-exposed cardiomyocytes in vitro. Overexpression of iASPP reduced the infarct size and cardiomyocyte apoptosis of mice subjected to 24 h of coronary artery ligation. Echocardiography showed that cardiac function was improved as indicated by the increase in ejection fraction and fractional shortening. In contrast, knockdown of iASPP exacerbated cardiac injury as manifested by impaired cardiac function, increased infarct size, and apoptosis rate. Mechanistically, overexpression of iASPP inhibited, while knockdown of iASPP increased the expressions of p53 and Bax, the key regulators of apoptosis. Taken together, our results suggested that iASPP is an important regulator of cardiomyocyte apoptosis, which represents a potential target in the therapy of myocardial infarction.

Labeled-free quantitative proteomic analysis of cervical squamous cell carcinoma identifies potential protein biomarkers

“…As the third member of the TP53 apoptosis stimulating protein family, its role is to inhibit the anti-tumor effect of the other two members (ASPP1 and ASPP2), leading to abnormal cell proliferation and carcinogenesis ( Li et al, 2024 ). Accordingly, it was generally believed that PPP1R13L as a novel oncogene highly expressed in a variety of tumor cells ( Yagudin et al, 2021 ). Protein Phosphatase 1 Regulatory Subunit 13 Like (PPP1R13L) is a newly identified oncoprotein previously reported to inhibit the transcriptional activity of SP1 via a direct protein-protein interaction) ( Zhang et al, 2022 ).…”

Hypoxia triggers cardiomyocyte apoptosis via regulating the m6A methylation-mediated LncMIAT/miR-708-5p/p53 axis

“…Generally, p53 serves to activate the tumor suppressor, mouse double minute 2 and PTEN expression-induced apoptosis [ 39 ]. In the myocardium, the activation of p53 was shown to aggravate MI injury and to increase the level of apoptosis, as determined by changes to the Bax/Bcl-2 ratio and caspase-3 activation [ 11 , 40 ]. In the present study, the level of p53 was measured to determine how the hypoxia stimulus could regulate p53-induced apoptosis in cardiomyocytes.…”

Interdependent Nuclear Co-Trafficking of ASPP1 and p53 Aggravates Cardiac Ischemia/Reperfusion Injury

“…Consistent with the different influence of iASPP on p53 expression and distribution than ASPP1, knockdown of iASPP aggravates cardiac ischemic damage. 10…”

“…Consistent with the different influence of iASPP on p53 expression and distribution than ASPP1, knockdown of iASPP aggravates cardiac ischemic damage. 10 The proapoptotic effect of ASPP1 depends on its nuclear localization. Arnaud et al 33 reported that unlike in the nucleus, cytoplasmic ASPP1 competed with YAP (Yes-associated protein) for LATS2 (large tumor suppressor homolog 2) and inhibited the phosphorylation of YAP, thereby exerting an antiapoptotic effect.…”

“…8,9 In a previous study, we proved the antiapoptotic effects of iASPP in cardiomyocytes, which alleviated myocardial ischemia injury by inhibiting p53 expression. 10 ASPP1 is crucial in improving the transcriptional activity of p53 in the nucleus. 11 Knockdown of ASPP1 blocks the apoptosis of renal clear cell carcinoma by inhibiting the transcriptional activation of p53.…”