AMPK activation restores ischemic post‑conditioning cardioprotection in STZ‑induced type 1 diabetic rats: Role of autophagy

Zhou,Bin; Leng,Yan; Lei,Shao‑Qing; Xia,Zhong‑Yuan

doi:10.3892/mmr.2017.7033

AMPK activation restores ischemic post‑conditioning cardioprotection in STZ‑induced type 1 diabetic rats: Role of autophagy

Authors:
- Bin Zhou
- Yan Leng
- Shao‑Qing Lei
- Zhong‑Yuan Xia
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Affiliations: Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: July 18, 2017 https://doi.org/10.3892/mmr.2017.7033
Pages: 3648-3656

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Abstract

Although the mechanism remains unclear, ischemic post‑conditioning (IPO) is a promising approach to combat myocardial ischemia reperfusion (IR) injury; however, it has been proven ineffective in diabetes. The present study aimed to identify whether hyperglycemia‑induced AMP‑activated protein kinase (AMPK) inhibition contributes to the ineffectiveness of IPO via autophagy attenuation in diabetic hearts. Diabetic and non‑diabetic rats were subjected to myocardial IR and/or IPO with/without treatment with the AMPK activator A‑769662 and/or autophagy inhibitor 3‑methyladenine (3‑MA). Rat cardiomyocyte H9c2 cells were pretreated with A‑769662 and/or 3‑MA, and subjected to hypoxia reoxygenation (HR) or hypoxia post‑conditioning (HPO). The degree of injury to the myocardium/cells, oxidative stress, AMPK/mammalian target of rapamycin (mTOR) signaling and autophagy status were analyzed. In diabetic rats the myocardial infarct size, and creatine kinase‑MB and malondialdehyde release, were increased compared with non‑diabetic rats, concomitant with increased cardiac dysfunction and decreased cardiac superoxide dismutase activity, AMPK phosphorylation and autophagy following IR. IPO attenuated myocardial infarct size, increased AMPK phosphorylation and enhanced autophagy in non‑diabetic animals. A‑769662 (6.0 mg/kg) restored IPO cardioprotection in diabetic rats. In vitro, HPO combined with A‑769662 decreased HR injury in H9c2 cells exposed to high glucose, as evidenced by decreased lactic dehydrogenase expression and oxidative stress, accompanied by increased cell viability and autophagy. The A‑769662‑mediated restoration of IPO/HPO cardioprotection was completely reversed by treatment with the autophagy inhibitor 3‑MA. In conclusion, AMPK inhibition, by decreasing autophagy, may be a mechanism through which diabetic hearts are rendered unresponsive to IPO cardioprotection.

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