4.5 Article

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

期刊

MOLECULAR MEDICINE REPORTS
卷 25, 期 3, 页码 -

出版社

SPANDIDOS PUBL LTD
DOI: 10.3892/mmr.2022.12596

关键词

remote ischemic preconditioning; prolyl 4-hydroxylase; hypoxia-inducible factor-1 alpha; ischemia/reperfusion; cardiac injury

资金

  1. Jiangxi Provincial Natural Science Foundation Project [20171BBG70067, 20181074]
  2. National Natural Science Foundation of China [81160019, 81360031]

向作者/读者索取更多资源

This study found that remote ischemic preconditioning (RIP) and prolyl 4-hydroxylase (PHD) inhibitor dimethyloxalylglycine (DMOG) exerted synergistic protective effects on myocardial injury induced by ischemia/reperfusion (I/R). Mechanistically, these protective effects were achieved through the activation of HIF-1 alpha and its downstream VEGF/AKT-eNOS signaling pathway.
It has been reported that hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha 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-1 alpha and the downstream VEGF/AKT-eNOS signaling pathway.

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