Synergetic protective effect of remote ischemic preconditioning and prolyl 4‑hydroxylase inhibition in ischemic cardiac injury

Yang,Juesheng; Xu,Jiajun; Tao,Lei; Wang,Shiyong; Xiang,Haiyan; Tang,Yanhua

doi:10.3892/mmr.2022.12596

Synergetic protective effect of remote ischemic preconditioning and prolyl 4‑hydroxylase inhibition in ischemic cardiac injury

Authors:
- Juesheng Yang
- Jiajun Xu
- Lei Tao
- Shiyong Wang
- Haiyan Xiang
- Yanhua Tang
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Affiliations: Department of Cardiovascular Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330036, P.R. China, Department of Cardiothoracic Surgery, Jiujiang No. 1 People's Hospital, Jiujiang, Jiangxi 332000, P.R. China, Department of Bone and Soft Tissue Oncology, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi 330006, P.R. China, Department of Clinical Medicine, Medical College of Nanchang University, Nanchang, Jiangxi 330036, P.R. China
Published online on: January 11, 2022 https://doi.org/10.3892/mmr.2022.12596
Article Number: 80
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has been reported that hypoxia‑inducible factor 1α (HIF‑1α) serves a key role in the protective effect of remote ischemic preconditioning (RIP) in ischemia/reperfusion (I/R)‑induced cardiac injury. Moreover, inhibition of prolyl 4‑hydroxylase (PHD), an enzyme responsible for HIF‑1α degradation, prevents I/R‑induced cardiac injury. However, whether their protective effects are synergetic remains to be elucidated. The present study aimed to investigate the protective effect of RIP, PHD inhibition using dimethyloxalylglycine (DMOG) and their combination on I/R‑induced cardiac injury. Rabbits were randomly divided into seven groups: i) Sham; ii) I/R; iii) lung RIP + I/R; iv) thigh RIP + I/R; v) DMOG + I/R; vi) DMOG + lung RIP + I/R; and vii) DMOG + thigh RIP + I/R. I/R models were established via 30 min left coronary artery occlusion and 3 h reperfusion. For lung/thigh RIP, rabbits received left pulmonary artery (or left limb) ischemia for 25 min and followed by release for 5 min. Some rabbits were administered 20 mg/kg DMOG. The results demonstrated that both lung/thigh RIP and DMOG significantly decreased myocardial infarct size, creatine kinase activity and myocardial apoptosis in I/R rabbits. Furthermore, the combination of RIP and PHD inhibition exerted synergetic protective effects on these aforementioned changes. The mechanistic study indicated that both treatments increased mRNA and protein expression levels of HIF‑1α and its downstream regulators, including vascular endothelial growth factor (VEGF), AKT and endothelial nitric oxide synthase (eNOS). In conclusion, the present study demonstrated that RIP and PHD inhibition exerted synergetic protective effects on cardiac injury via activation of HIF‑1α and the downstream VEGF/AKT‑eNOS signaling pathway.

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