Abstract
Purpose:To investigate whether GDF11 ameliorates myocardial ischemia reperfusion (MIR) injury in diabetic rats and explore the underlying mechanisms.Methods:Diabetic and non-diabetic rats subjected to MIR (30 min of coronary artery occlusion followed by 120 min of reperfusion) with/without GDF11 pretreatment. Cardiac function, myocardial infarct size, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), superoxide dismutase (SOD) 15-F2tisoprostane, autophagosome, LC3II/I ratio and Belcin-1 level were determined to reflect myocardial injury, oxidative stress and autophagy, respectively. In in vitro study, H9c2 cells cultured in high glucose (HG, 30mM) suffered hypoxia reoxygenation (HR) with/without GDF11, hydrogen peroxide (H2O2) and autophagy inhibitor 3-methyladenine (3-MA) treatment, cell injury; oxidative stress and autophagy were assessed.Results:Pretreatment with GDF11 significantly improved cardiac morphology and function in diabetes, concomitant with decreased arrhythmia severity, infarct size, CK-MB, LDH and 15-F2tisoprostane release, increased SOD activity and autophagy level. In addition, GDF11 notably reduced HR injury in H9c2 cells with HG exposure, accompanied by oxidative stress reduction and autophagy up-regulation. However, those effects were completely reversed by H2O2 and 3-MA.Conclusion:GDF11 can provide protection against MIR injury in diabetic rats, and is implicated in antioxidant stress and autophagy up-regulation.
Highlights
The incidence of diabetes has increased rapidly in recent decades; the latest data from the International Diabetes Federation showed that the number of adult diabetic patients worldwide is more than 415 million
Our previously studies have shown that the exacerbated oxidative stress regulates cell signaling involved in types of cellular death in the process of diabetic myocardial ischemia reperfusion (MIR) injury, which may be responsible for the increased vulnerability of the diabetic myocardium[4,5]
To further verify the function of Growth differentiation factor 11 (GDF11) in the above process 3-MA, the autophagy inhibitor was administrated after GDF11 pretreatment, and our results showed that the protections provided by GDF11 were totally reversed by treatment with 3-MA
Summary
The incidence of diabetes has increased rapidly in recent decades; the latest data from the International Diabetes Federation showed that the number of adult diabetic patients worldwide is more than 415 million. It has become a global public health problem, endangering human health and increasing social burden. Our previously studies have shown that the exacerbated oxidative stress regulates cell signaling involved in types of cellular death in the process of diabetic MIR injury, which may be responsible for the increased vulnerability of the diabetic myocardium[4,5]. It is urgent to discuss how to decrease oxidative stress and up-regulate autophagy in the diabetic myocardium, as this is beneficial to ameliorate MIR in diabetes and could provide prevention and therapy strategies for clinical practice
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