HSPA12A Stimulates p38/ERK-AP-1 Signaling to Promote Angiogenesis and Is Required for Functional Recovery Postmyocardial Infarction

Abstract

Angiogenesis plays a critical role in wound healing postmyocardial infarction (MI). However, there is still a lack of ideal angiogenic therapeutics for rescuing ischemic hearts clinically, suggesting that a more understanding regarding angiogenesis regulation is urgently needed. Heat shock protein A12A (HSPA12A) is an atypical member of the HSP70 family. Here, we demonstrated that HSPA12A was upregulated during endothelial tube formation, a characteristic of in vitro angiogenesis. Intriguingly, overexpression of HSPA12A promoted in vitro angiogenic characteristics including proliferation, migration, and tube formation of endothelial cells. By contrast, deficiency of HSPA12A impaired myocardial angiogenesis and worsened cardiac dysfunction post-MI in mice. The expression of genes related to angiogenesis (VEGF, VEGFR2, and Ang-1) was decreased by HSPA12A deficiency in MI hearts of mice, whereas their expression was increased by HSPA12A overexpression in endothelial cells. HSPA12A overexpression in endothelial cells increased phosphorylation levels and nuclear localization of AP-1, a transcription factor dominating angiogenic gene expression. Also, HSPA12A increased p38 and ERK phosphorylation levels, whereas inhibition of p38 or ERKs diminished the HSPA12A-promoted AP-1 phosphorylation and nuclear localization, as well as VEGF and VEGFR2 expression in endothelial cells. Notably, inhibition of either p38 or ERKs diminished the HSPA12A-promoted in vitro angiogenesis characteristics. The findings identified HSPA12A as a novel angiogenesis activator, and HSPA12A might represent a viable strategy for the management of myocardial healing in patients with ischemic heart diseases.