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

Sanit,Jantira; Prompunt,Eakkapote; Adulyaritthikul,Punyanuch; Nokkaew,Nuttikarn; Mongkolpathumrat,Podsawee; Kongpol,Kantapich; Kijtawornrat,Anusak; Petchdee,Soontaree; Barrère‑Lemaire,Stephanie; Kumphune,Sarawut

doi:10.3892/etm.2019.7763

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

Authors:
- Jantira Sanit
- Eakkapote Prompunt
- Punyanuch Adulyaritthikul
- Nuttikarn Nokkaew
- Podsawee Mongkolpathumrat
- Kantapich Kongpol
- Anusak Kijtawornrat
- Soontaree Petchdee
- Stephanie Barrère‑Lemaire
- Sarawut Kumphune
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Affiliations: Biomedical Research Unit in Cardiovascular Sciences (BRUCS), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand, Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10240, Thailand, Department of Large Animal and Wildlife Clinical Science, Faculty of Veterinary Medicine, Kasetsart University, Nakhorn Pathom 73140, Thailand, IGF, CNRS, INSERM, University of Montpellier, 34094 Montpellier, France
Published online on: July 10, 2019 https://doi.org/10.3892/etm.2019.7763
Pages: 1701-1714
Copyright: © Sanit et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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