Title:The Newly Proposed Mechanism of Cardiomyocyte Protection of Carvedilol-
Anti-Apoptosis Pattern of Carvedilol in Anoxia by Inducing Autophagy
Partly through the AMPK/mTOR Pathway
Volume: 20
Issue: 10
Author(s): Jingru Li, Chaozhong Li, Guihu Sun, Longjun Li, Yongli Zeng, Huawei Wang, Xinyu Wu, Ping Yang, Yunzhu Peng*Luqiao Wang*
Affiliation:
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
Keywords:
Carvedilol, autophagy, anoxia, apoptosis, AMPK/mTOR signal pathway, cardiomyocyte protection.
Abstract:
Purpose: To investigate the underlying mechanism of cardiomyocyte protection of carvedilol
based on autophagy and apoptosis.
Methods: Neonatal rat ventricular myocytes (NRVMs) were exposed to various concentrations of carvedilol
before anoxia, and pretreated with 3-MA or compound C for inhibiting autophagy or p-AMPK expression.
CCK-8 colorimeter and flow cytometry were used to determine the cell viability and apoptotic
rates. The variation of mRNA and protein was measured by RT-PCR and Western blot. The presence of
autophagosomes was observed by electron microscopy.
Results: First, we found that carvedilol increased autophagic marker levels in a concentration-dependent
manner and the number of autophagosomes in NRVMs. Moreover, carvedilol substantially enhanced the
viability and noticeably reduced the CK, MDA and LDH levels and cell apoptosis rate compared with the
anoxia group. In addition, carvedilol decreased the levels of caspase-3 and Bim in mRNA and protein, but
such effect was blocked by the special autophagy inhibitor-3-MA, and the number of autophagosomes
was significantly decreased when treated with 3-MA, indicating that carvedilol exhibited anti-apoptotic
and anti-injury effects by inducing autophagy in anoxia NRVMs, but these effects can be abolished by
adding 3-MA to suppress autophagy. Finally, the carvedilol treatment-induced autophagy by enhancing
the activation of p-AMPK and inhibiting p-mTOR. Electron microscopy presented that the number of
autophagosomes was significantly decreased when treating with compound C, indicating that carvedilol
induced autophagy in anoxia NRVMs partly by the AMPK-mTOR signaling pathway.
Conclusion: Carvedilol has cardioprotection by inducing autophagy against apoptosis partly through the
AMPK/mTOR pathway during anoxia in NRVMs.
