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C-reactive protein accelerates DRP1-mediated mitochondrial fission by modulating ERK1/2-YAP signaling in cardiomyocytes.
Suyeon Jin 1,2,# (Graduate student), Chan Joo Lee 1,# (Professor), Gibbeum Lim 1 (Research worker), Sungha Park 1 (Professor), Sang-Hak Lee1 (Professor), Ji Hyung Chung (Professor), Jaewon Oh 1 (Professor), Seok-Min Kang 1,* (Professor)
1Cardiology, Severance Cardiovascular Hospital, Cardiovascular Research Institute, Yonsei University College of Medicine,
2Graduate Program in Biomedical Engineering, Yonsei University College of Medicine,
3Department of Applied Bioscience, College of Life Science, CHA University
C-reactive protein (CRP) is an inflammatory marker and risk factor for atherosclerosis and cardiovascular diseases. However, the mechanism through which CRP induces myocardial damage remains unclear. This study aimed to determine how CRP damages cardiomyocytes via the change of mitochondrial dynamics and whether survivin, an anti-apoptotic protein, exerts a cardioprotective effect in this process. We treated H9c2 cardiomyocytes with CRP and found increased intracellular ROS production and shortened mitochondrial length. CRP treatment phosphorylated ERK1/2 and promoted increased expression, phosphorylation, and translocation of DRP1, a mitochondrial fission-related protein, from the cytoplasm to the mitochondria. The expression of mitophagy proteins PINK1 and PARK2 was also increased by CRP. YAP, a transcriptional regulator of PINK1 and PARK2, was also increased by CRP. Knockdown of YAP prevented CRP-induced increases in DRP1, PINK1, and PARK2. Furthermore, CRP-induced changes in the expression of DRP1 and increases in YAP, PINK1, and PARK2 were inhibited by ERK1/2 inhibition, suggesting that ERK1/2 signaling is involved in CRP-induced mitochondrial fission. We treated H9c2 cardiomyocytes with a recombinant TAT-survivin protein before CRP treatment, which reduced CRP-induced ROS accumulation and reduced mitochondrial fission. CRP-induced activation of ERK1/2 and increases in the expression and activity of YAP and its downstream mitochondrial proteins were inhibited by TAT-survivin. This study shows that mitochondrial fission occurs during CRP-induced cardiomyocyte damage and that the ERK1/2-YAP axis is involved in this process, and identifies that survivin alters these mechanisms to prevent CRP-induced mitochondrial damage.
Abstract, Accepted Manuscript(in press) [Submitted on July 17, 2023, Accepted on September 13, 2023]
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