SerpinB1 promotes cardiomyocyte proliferation and heart regeneration via inhibiting ERBB2 degradation

Abstract

Adult hearts are hard to recover after injury due to postnatal loss of regenerative capacity. Induction of cell cycle reentry of adult cardiomyocytes by special treatment offers a promising regenerative therapy for heart injury. This study aims to investigate the role of serpin family B member 1 (SerpinB1) in the regulation of cardiomyocyte proliferation and heart regeneration. The expression of SerpinB1 in the mouse heart was decreased during postnatal growth and increased during neonatal heart regeneration induced by apical resection (AR), consistent with the alteration of regenerative capacity. Cardiac-specific overexpression of SerpinB1 reactivated cardiomyocyte proliferation and improved cardiac repair following myocardial infarction (MI) in adult mice. Mechanistically, we found erb-b2 receptor tyrosine kinase 2 (ERBB2) signaling activity was upregulated by SerpinB1 overexpression and administration of ERBB2 kinase inhibitor AG789 largely blunted cardiomyocyte pro-proliferative effect of SerpinB1. Further study revealed that SerpinB1 upregulated ERBB2 protein level via interacting with elastase to inhibit ERBB2 degradation and elastase overexpression blocked SerpinB1-induced cardiomyocyte proliferation in vitro. Taken together, these results highlight SerpinB1 as a critical regulator of cardiomyocyte proliferation. SerpinB1 targeting might be a novel potential therapeutic strategy for cardiac regeneration after heart injury.