BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

C-reactive protein accelerates DRP1-mediated mitochondrial fission by modulating ERK1/2-YAP signaling in cardiomyocytes

  • Suyeon Jin (Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine) ;
  • Chan Joo Lee (Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine) ;
  • Gibbeum Lim (Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine) ;
  • Sungha Park (Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine) ;
  • Sang-Hak Lee (Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine) ;
  • Ji Hyung Chung (Department of Applied Bioscience, College of Life Science, CHA University) ;
  • Jaewon Oh (Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine) ;
  • Seok-Min Kang (Division of Cardiology, Department of Internal Medicine, Severance Cardiovascular Hospital, Yonsei University College of Medicine)
  • Received : 2023.07.17
  • Accepted : 2023.09.13
  • Published : 2023.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

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.

Keywords

Acknowledgement

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B03935941, NRF-2022R1A2C1093325).

References

  1. Bisoendial RJ, Boekholdt SM, Vergeer M, Stroes ES and Kastelein JJ (2010) C-reactive protein is a mediator of cardiovascular disease. Eur Heart J 31, 2087-2091 https://doi.org/10.1093/eurheartj/ehq238
  2. Anand IS, Latini R, Florea VG et al (2005) C-reactive protein in heart failure: prognostic value and the effect of valsartan. Circulation 112, 1428-1434 https://doi.org/10.1161/CIRCULATIONAHA.104.508465
  3. Ridker PM, Glynn RJ and Hennekens CH (1998) C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 97, 2007-2011 https://doi.org/10.1161/01.CIR.97.20.2007
  4. Wilson PW, Pencina M, Jacques P, Selhub J, D'Agostino R Sr and O'Donnell CJ (2008) C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circ Cardiovasc Qual Outcomes 1, 92-97 https://doi.org/10.1161/CIRCOUTCOMES.108.831198
  5. Verma S, Kuliszewski MA, Li SH et al (2004) C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease. Circulation 109, 2058-2067 https://doi.org/10.1161/01.CIR.0000127577.63323.24
  6. Nagai T, Anzai T, Kaneko H et al (2011) C-reactive protein overexpression exacerbates pressure overload-induced cardiac remodeling through enhanced inflammatory response. Hypertension 57, 208-215 https://doi.org/10.1161/HYPERTENSIONAHA.110.158915
  7. Yang J, Wang J, Zhu S et al (2008) C-reactive protein augments hypoxia-induced apoptosis through mitochondrion-dependent pathway in cardiac myocytes. Mol Cell Biochem 310, 215-226 https://doi.org/10.1007/s11010-007-9683-3
  8. Zhou B and Tian R (2018) Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest 128, 3716-3726 https://doi.org/10.1172/JCI120849
  9. Bravo-San Pedro JM, Kroemer G and Galluzzi L (2017) Autophagy and mitophagy in cardiovascular disease. Circ Res 120, 1812-1824 https://doi.org/10.1161/CIRCRESAHA.117.311082
  10. Vasquez-Trincado C, Garcia-Carvajal I, Pennanen C et al (2016) Mitochondrial dynamics, mitophagy and cardiovascular disease. J Physiol 594, 509-525 https://doi.org/10.1113/JP271301
  11. Sciarretta S, Maejima Y, Zablocki D and Sadoshima J (2018) The Role of Autophagy in the Heart. Annu Rev Physiol 80, 1-26 https://doi.org/10.1146/annurev-physiol-021317-121427
  12. Zhong Y, Cheng CF, Luo YZ et al (2015) C-reactive protein stimulates RAGE expression in human coronary artery endothelial cells in vitro via ROS generation and ERK/NF-κB activation. Acta Pharmacol Sin 36, 440-447 https://doi.org/10.1038/aps.2014.163
  13. Athanasoula K, Gogas H, Polonifi K, Vaiopoulos AG, Polyzos A and Mantzourani M (2014) Survivin beyond physiology: orchestration of multistep carcinogenesis and therapeutic potentials. Cancer Lett 347, 175-182 https://doi.org/10.1016/j.canlet.2014.02.014
  14. Lee BS, Kim SH, Oh J et al (2014) C-reactive protein inhibits survivin expression via Akt/mTOR pathway down-regulation by PTEN expression in cardiac myocytes. PLoS One 9, e98113
  15. Lee BS, Kim SH, Jin T et al (2013) Protective effect of survivin in Doxorubicin-induced cell death in h9c2 cardiac myocytes. Korean Circ J 43, 400-407 https://doi.org/10.4070/kcj.2013.43.6.400
  16. Shen YL, Shi YZ, Chen GG et al (2018) TNF-α induces Drp1-mediated mitochondrial fragmentation during inflammatory cardiomyocyte injury. Int J Mol Med 41, 2317-2327 https://doi.org/10.3892/ijmm.2018.3385
  17. Huang CY, Lai CH, Kuo CH et al (2018) Inhibition of ERK-Drp1 signaling and mitochondria fragmentation alleviates IGF-IIR-induced mitochondria dysfunction during heart failure. J Mol Cell Cardiol 122, 58-68 https://doi.org/10.1016/j.yjmcc.2018.08.006
  18. Vives-Bauza C, Zhou C, Huang Y et al (2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci U S A 107, 378-383 https://doi.org/10.1073/pnas.0911187107
  19. Leach JP, Heallen T, Zhang M et al (2017) Hippo pathway deficiency reverses systolic heart failure after infarction. Nature 550, 260-264 https://doi.org/10.1038/nature24045
  20. Singh U, Devaraj S, Vasquez-Vivar J and Jialal I (2007) C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling. J Mol Cell Cardiol 43, 780-791 https://doi.org/10.1016/j.yjmcc.2007.08.015
  21. Han C, Liu J, Liu X and Li M (2010) Angiotensin II induces C-reactive protein expression through ERK1/2 and JNK signaling in human aortic endothelial cells. Atherosclerosis 212, 206-212 https://doi.org/10.1016/j.atherosclerosis.2010.05.020
  22. Choi JW, Lee KH, Kim SH et al (2011) C-reactive protein induces p53-mediated cell cycle arrest in H9c2 cardiac myocytes. Biochem Biophys Res Commun 410, 525-530 https://doi.org/10.1016/j.bbrc.2011.06.016
  23. Adaniya SM, J OU, Cypress MW, Kusakari Y and Jhun BS (2019) Posttranslational modifications of mitochondrial fission and fusion proteins in cardiac physiology and pathophysiology. Am J Physiol Cell Physiol 316, C583-C604 https://doi.org/10.1152/ajpcell.00523.2018
  24. Chen Y, Liu Y and Dorn GW, 2nd (2011) Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res 109, 1327-1331 https://doi.org/10.1161/CIRCRESAHA.111.258723
  25. Tai P and Ascoli M (2011) Reactive oxygen species (ROS) play a critical role in the cAMP-induced activation of Ras and the phosphorylation of ERK1/2 in Leydig cells. Mol Endocrinol 25, 885-893 https://doi.org/10.1210/me.2010-0489
  26. Li H, He F, Zhao X et al (2017) YAP inhibits the apoptosis and migration of human rectal cancer cells via suppression of JNK-Drp1-mitochondrial fission-HtrA2/Omi pathways. Cell Physiol Biochem 44, 2073-2089 https://doi.org/10.1159/000485946
  27. Lei Q, Tan J, Yi S, Wu N, Wang Y and Wu H (2018) Mitochonic acid 5 activates the MAPK-ERK-yap signaling pathways to protect mouse microglial BV-2 cells against TNFα-induced apoptosis via increased Bnip3-related mitophagy. Cell Mol Biol Lett 23, 14
  28. Fan S, Price T, Huang W et al (2020) PINK1-dependent mitophagy regulates the migration and homing of multiple myeloma cells via the MOB1B-mediated hippo-YAP/TAZ pathway. Adv Sci (Weinh) 7, 1900860
  29. Hagenbuchner J, Kuznetsov AV, Obexer P and Ausserlechner MJ (2013) BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery. Oncogene 32, 4748-4757 https://doi.org/10.1038/onc.2012.500