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GRK2 deletion improves the function of skin flap following ischemia-reperfusion injury by regulating Drp1.

ABSTRACT: Skin flap ischemia-reperfusion (IR) injury is the key factor to the success rate of skin transplantation, the molecular mechanism of flap IR injury needs to be continuously explored to provide new ideas for its clinical treatment. G protein-coupled receptor kinase 2 (GRK2) was reported to be involved in regulating mitochondrial function, and mitochondria were essential in the process of flap IR. Thus, we aimed to investigate the function of GRK2 in flap ischemia-reperfusion injury and further explore the underlying mechanism. Sixty male C57BL/6 mice were randomly divided into four groups: sham, IR+sh-NC, IR+sh-GRK2 and IR+sh-GRK2+ dynamin-related GTPase 1 (Drp1). Flap function and mitochondrial function were determined after ischemia for 3 hours and reperfusion for 72 hours. Comparing with sham group, GRK2 was increased in flap after IR injury. Loss of GRK2 inhibited cell apoptosis and promoted cell proliferation of flap after IR injury. And deficiency of GRK2 promoted mitochondrial function in flap after IR injury. IR injury up-regulated Drp1 expression in flap, while sh-GRK2 down-regulated Drp1 expression. Furthermore, overexpression of Drp1 removed the protective effect of sh-GRK2. In conclusion, our study revealed that GRK2 deletion improved flap function and mitochondrial function by inhibiting Drp1 expression, which may provide a new insight for the clinical treatment of flap ischemia-reperfusion injury.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7847531 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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GRK2 deletion improves the function of skin flap following ischemia-reperfusion injury by regulating Drp1.

Wang Yapeng Y Wu Yongwei Y Zhou Ming M Wang Peng P Luo Junhao J Rui Yongjun Y

American journal of translational research 20210115 1

Skin flap ischemia-reperfusion (IR) injury is the key factor to the success rate of skin transplantation, the molecular mechanism of flap IR injury needs to be continuously explored to provide new ideas for its clinical treatment. G protein-coupled receptor kinase 2 (GRK2) was reported to be involved in regulating mitochondrial function, and mitochondria were essential in the process of flap IR. Thus, we aimed to investigate the function of GRK2 in flap ischemia-reperfusion injury and further ex ...[more]

PMID: 33527020

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Project description:Mitochondrial dysfunction is a salient feature of myocardial ischemia/reperfusion injury (MIRI), while the potential mechanism of mitochondrial dynamics disorder remains unclear. This study sought to explore whether activation of Adenosine monophosphate-activated protein kinase (AMPK) could alleviate MIRI by regulating GTPase dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics. Isolated mouse hearts in a Langendorff perfusion system were subjected to ischemia/reperfusion (I/R) treatment, and H9C2 cells were subjected to hypoxia /reoxygenation (H/R) treatment in vitro. The results showed that AICAR, the AMPK activator, could significantly improve the function of left ventricular, decrease arrhythmia incidence and myocardial infarction area of isolated hearts. Meanwhile, AICAR increased superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) content in myocardial homogenate. Mechanistically, AICAR inhibited the phosphorylation of Drp1 at Ser 616 while enhanced phosphorylation of Drp1 at Ser 637. In addition, AICAR reduced the expression of inflammatory cytokines including TNF-ɑ, IL-6, and IL-1β, as well as mitochondrial fission genes Mff and Fis1, while improved the expression of mitochondrial fusion genes Mfn1 and Mfn2. Similar results were also observed in H9C2 cells. AICAR improved mitochondrial membrane potential (MMP), reduced reactive oxygen species (ROS) production, and inhibited mitochondrial damage. To further prove if Drp1 regulated mitochondrial dynamics mediated AMPK protection effect, the mitochondrial fission inhibitor Mdivi-1 was utilized. We found that Mdivi-1 significantly improved MMP, inhibited ROS production, reduced the expression of TNF-a, IL-6, IL-1β, Fis1, and Mff, and improved the expression of Mfn1 and Mfn2. However, the protection effect of Mdivi-1 was not reversed by AMPK inhibitor Compound C. In conclusion, this study confirmed that activation of AMPK exerted the protective effects on MIRI, which were largely dependent on the inhibition of Drp1-mediated mitochondrial fission.

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GRK2 deletion improves the function of skin flap following ischemia-reperfusion injury by regulating Drp1.

Publications

GRK2 deletion improves the function of skin flap following ischemia-reperfusion injury by regulating Drp1.

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