C-reactive protein accelerates DRP1-mediated mitochondrial fission by modulating ERK1/2-YAP signaling in cardiomyocytes
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C-reactive protein (CRP) is an inflammatory marker and risk factorfor atherosclerosis and cardiovascular diseases. However, themechanism through which CRP induces myocardial damage remainsunclear. This study aimed to determine how CRP damagescardiomyocytes via the change of mitochondrial dynamics andwhether survivin, an anti-apoptotic protein, exerts a cardioprotectiveeffect in this process. We treated H9c2 cardiomyocyteswith CRP and found increased intracellular ROS production andshortened mitochondrial length. CRP treatment phosphorylatedERK1/2 and promoted increased expression, phosphorylation,and translocation of DRP1, a mitochondrial fission-related protein,from the cytoplasm to the mitochondria. The expressionof mitophagy proteins PINK1 and PARK2 was also increased byCRP. YAP, a transcriptional regulator of PINK1 and PARK2, wasalso increased by CRP. Knockdown of YAP prevented CRP-inducedincreases in DRP1, PINK1, and PARK2. Furthermore,CRP-induced changes in the expression of DRP1 and increasesin YAP, PINK1, and PARK2 were inhibited by ERK1/2 inhibition,suggesting that ERK1/2 signaling is involved in CRP-inducedmitochondrial fission. We treated H9c2 cardiomyocyteswith a recombinant TAT-survivin protein before CRP treatment,which reduced CRP-induced ROS accumulation and reducedmitochondrial fission. CRP-induced activation of ERK1/2 andincreases in the expression and activity of YAP and its downstreammitochondrial proteins were inhibited by TAT-survivin. This study shows that mitochondrial fission occurs during CRPinducedcardiomyocyte damage and that the ERK1/2-YAP axisis involved in this process, and identifies that survivin altersthese mechanisms to prevent CRP-induced mitochondrial damage.
Abstract
C-reactive protein (CRP) is an inflammatory marker and risk factorfor atherosclerosis and cardiovascular diseases. However, themechanism through which CRP induces myocardial damage remainsunclear. This study aimed to determine how CRP damagescardiomyocytes via the change of mitochondrial dynamics andwhether survivin, an anti-apoptotic protein, exerts a cardioprotectiveeffect in this process. We treated H9c2 cardiomyocyteswith CRP and found increased intracellular ROS production andshortened mitochondrial length. CRP treatment phosphorylatedERK1/2 and promoted increased expression, phosphorylation,and translocation of DRP1, a mitochondrial fission-related protein,from the cytoplasm to the mitochondria. The expressionof mitophagy proteins PINK1 and PARK2 was also increased byCRP. YAP, a transcriptional regulator of PINK1 and PARK2, wasalso increased by CRP. Knockdown of YAP prevented CRP-inducedincreases in DRP1, PINK1, and PARK2. Furthermore,CRP-induced changes in the expression of DRP1 and increasesin YAP, PINK1, and PARK2 were inhibited by ERK1/2 inhibition,suggesting that ERK1/2 signaling is involved in CRP-inducedmitochondrial fission. We treated H9c2 cardiomyocyteswith a recombinant TAT-survivin protein before CRP treatment,which reduced CRP-induced ROS accumulation and reducedmitochondrial fission. CRP-induced activation of ERK1/2 andincreases in the expression and activity of YAP and its downstreammitochondrial proteins were inhibited by TAT-survivin. This study shows that mitochondrial fission occurs during CRPinducedcardiomyocyte damage and that the ERK1/2-YAP axisis involved in this process, and identifies that survivin altersthese mechanisms to prevent CRP-induced mitochondrial damage.
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