Combination of metformin and p38 MAPK inhibitor, SB203580, reduced myocardial ischemia/reperfusion injury in non‑obese type 2 diabetic Goto‑Kakizaki rats

Abstract

Diabetic cardiomyopathy, especially myocardial ischemia reperfusion (I/R) injury, is a major cause of morbidity and mortality in type 2 diabetic patients. The increasing of basal p38 MAP Kinase (p38 MAPK) activation is a major factor that aggravates cardiac death on diabetic cardiomyopathy. In addition, metformin also shows cardio-protective effects on myocardial ischemia/reperfusion injury. In this study, we investigated the effect of the combination between metformin and p38 MAPK inhibitor (SB203580) in diabetic rats subjected to I/R injury. H9c2 cells were induced into a hyperglycemic condition and treated with metformin, SB203580 or the combination of metformin and SB203580. In addition, cells in both the presence and absence of drug treatment were subjected to simulated ischemia/reperfusion injury. Cell viability and cellular reactive oxygen species (ROS) were determined. Moreover, the Goto-Kakizaki (GK) rats were treated with metformin, SB203580, and the combination of metformin and SB203580 for 4 weeks. Diabetic parameters and cardiac functions were assessed. Finally, rat hearts were induced ischemia/reperfusion injury for the purpose of infarct size analysis and determination of signal transduction. A high-glucose condition did not reduce cell viability but significantly increased ROS production and significantly decreased cell viability after induced sI/R. Treatment using drugs was shown to reduce ROS generation and cardiac cell death. The GK rats displayed diabetic phenotype by increasing diabetic parameters and these parameters were significantly decreased when treated with drugs. Treatment with metformin or SB203580 could significantly reduce the infarct size. Interestingly, the combination of metformin and SB203580 could enhance cardio-protective ability. Myocardial I/R injury significantly increased p38 MAPK phosphorylation, Bax/Bcl-2 ratio and caspase-3 level. Treatment with drugs significantly decreased the p38 MAPK phosphorylation, Bax/Bcl-2 ratio, caspase-3 level and increased Akt phosphorylation. In conclusion, using the combination of metformin and SB203580 shows positive cardio-protective effects on diabetic ischemic cardiomyopathy.

p38 MAPK Pathway in the Heart: New Insights in Health and Disease

“…The role of p38 in the control of intracellular Ca 2+ was corroborated in H9c2 cells: phosphodiesterase-inhibitor–mediated reduction in ERK1/2, JNK, and p38 activation reduced ischemia-induced apoptosis and restored normal calcium influx, oxidative stress levels, and eNOS expression [ 81 ]. p38 inhibition also potentiates the metformin-induced reduction in myocardial ischemia–reperfusion injury in non-obese type 2 diabetic rats [ 82 ].…”

Metformin Ameliorates Diabetic Cardiomyopathy by Activating the PK2/PKR Pathway

“…Met is also used in the treatment of diabetes complications such as DCM. Metformin ameliorates metabolic disorders, reduces ROS production and cardiac cell death, and improves myocardial structure and function on DCM (Sanit et al, 2019;Yang et al, 2019). Met also protects against brain and liver injury by activating AKT phosphorylation (Naicker et al, 2016;Xu et al, 2016).…”

GCN2 Regulates ATF3-p38 MAPK Signaling Transduction in Pulmonary Veno-Occlusive Disease

“…24 In non-obese type 2 diabetic Goto-Kakizaki rats, metformin or SB203580 can significantly reduce the size of myocardial infarction, and the combination of metformin and SB203580 can enhance the cardioprotection. 25…”