Abstract 17364: G-protein Signaling Regulation of the Hippo Pathway in Neonatal Heart Regeneration
| Autor: | Mei Xin, Aishlin Hassan, Masahide Sakabe |
|---|---|
| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Circulation. 142 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Introduction: The regeneration potential in the adult mammalian heart is very limited due to the cessation of cardiomyocyte proliferation shortly after birth. Recent studies have revealed that changes after birth such as metabolic state, oxygen level, cardiomyocyte structure and maturity, immune system and polyploidy are among the factors contributing to the loss of the regenerative potential in the heart. The mechanisms that regulate the cardiac regenerative window are not well understood. Here we report that G-protein mediated signaling regulates Hippo-YAP in neonatal cardiomyocyte proliferation and heart regeneration through Rho activity. Hypothesis: Gas encoded by the Gnas gene, a downstream effector of beta-adrenergic receptor (βAR) inhibits cardiomyocyte proliferation via regulation of YAP activity. Methods: We pharmacologically inhibited the G protein coupled receptor mediated β adrenergic signaling with a β-blocker (metoprolol) at early postnatal stages, and genetically by deleting Gnas in the heart with αMHC-Cre. We accessed the cardiomyocyte proliferation, heart regeneration in these mice and elucidated molecular mechanisms. Results: We found that β-blocker enhanced cardiomyocyte proliferation and promoted cardiac regeneration post cardiac injury with improved cardiac function. Consistent with β-blocker treated mice, mice lacking Gnas in cardiomyocytes exhibited enlarged hearts with an increase in cardiomyocyte proliferation. RNA-seq analysis revealed that these cardiomyocytes maintained an immature status even at young-adult age. The genes associated with mitochondrial oxidative metabolism, the major energy source for mature cardiomyocytes, were downregulated. Moreover, YAP activity was upregulated in both cases. We also found that loss of Gαs function caused upregulation of RhoA activity, and inhibitor of Rho signaling pathway suppressed the YAP activity in cardiomyocytes. Conclusions: Our study reveals that Gαs negatively regulate cardiomyocyte proliferation and provides mechanistic insight for β-blocker treatment as a strategy for inducing cardiac dedifferentiation and proliferation in injured heart. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|