Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul 03722; Graduate Program in Biomedical Engineering, Yonsei University College of Medicine, Seoul 03772, Korea.
Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul 03722, Korea.
BMB Rep. 2023 Dec;56(12):663-668. doi: 10.5483/BMBRep.2023-0127.
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 CRPinduced 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. [BMB Reports 2023; 56(12): 663-668].
C 反应蛋白（CRP）是炎症标志物和动脉粥样硬化及心血管疾病的危险因素。然而，CRP 诱导心肌损伤的机制尚不清楚。本研究旨在确定 CRP 通过改变线粒体动力学如何损伤心肌细胞，以及抗凋亡蛋白 survivin 是否在此过程中发挥心脏保护作用。我们用 CRP 处理 H9c2 心肌细胞，发现细胞内 ROS 产生增加，线粒体长度缩短。CRP 处理使 ERK1/2 磷酸化，并促进线粒体分裂相关蛋白 DRP1 从细胞质转位到线粒体，从而增加其表达、磷酸化和转位。CRP 还增加了 mitophagy 蛋白 PINK1 和 PARK2 的表达。YAP 是 PINK1 和 PARK2 的转录调节剂，也被 CRP 上调。YAP 敲低可阻止 CRP 诱导的 DRP1、PINK1 和 PARK2 增加。此外，CRP 诱导的 DRP1 表达变化和 YAP、PINK1 和 PARK2 的增加被 ERK1/2 抑制所抑制，表明 ERK1/2 信号参与了 CRP 诱导的线粒体分裂。我们在 CRP 处理前用重组 TAT-survivin 蛋白处理 H9c2 心肌细胞，减少了 CRP 诱导的 ROS 积累并减少了线粒体分裂。TAT-survivin 抑制了 CRP 诱导的 ERK1/2 激活以及 YAP 及其下游线粒体蛋白表达和活性的增加。本研究表明，线粒体分裂发生在 CRP 诱导的心肌细胞损伤过程中，ERK1/2-YAP 轴参与了这一过程，并确定 survivin 改变了这些机制，以防止 CRP 诱导的线粒体损伤。[BMB 报告 2023；56(12)：663-668]。
