Autophagy assuages myocardial infarction through Nrf2 signaling activation-mediated reactive oxygen species clear

B. Sun, Y. Xu, Z.-Y. Liu, W.-X. Meng, H. Yang

Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. redrosefive@163.com

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• Pharmacology

OBJECTIVE: The activation of autophagy was shown to shrink infarct size and mitigate cardiac dysfunction caused by myocardial infarction (MI). However, the underlying mechanisms remain largely unknown. As excessive generation of reactive oxygen species (ROS) deteriorates MI process and Nrf2 signaling exerts an antioxidant role, we explored whether autophagy assuaged MI through Nrf2 signaling activation-mediated ROS clear.

MATERIALS AND METHODS: MI models were induced by ligation of the left descending coronary artery (LAD) in C57BL/6J mice or Nrf2 knockout mice (Nrf2-KO). Rapamycin and 3-methyladenine (3-MA) were used to activate and repress autophagy in MI mice, respectively. Aspirin, a cardioprotective drug was given to MI mice to evaluate its effects on autophagy.

RESULTS: Compared with the MI group, rapamycin treatment remarkably decreased the infarct size, cell apoptosis and blood troponin I level, accompanied by reduced redox potential (Eh), ROS, malondialdehyde (MDA) and cytochrome C levels, and increased reduced glutathione (GSH) level. Also, rapamycin treatment increased the expressions of bcl-2, bcl-xL, HSP70, and HSP90. In addition, rapamycin treatment promoted the nuclear accumulation of Nrf2 protein. However, Nrf2 downregulation significantly impaired the effects of rapamycin on the reductions of infarct size, cell apoptosis, troponin I and ROS levels. Similarly, to rapamycin roles, aspirin treatment also remarkably reduced infarct size, cell apoptosis and troponin I in mice with MI surgery, as well as increased the expression level of LC3II/LC3I.

CONCLUSIONS: This study demonstrated that autophagy enhancement contributed to the improvement of MI through Nrf2 signaling activation-mediated ROS clear.

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