ISSN 1671-5411 CN 11-5329/R
Wei–Na PEI, Hai–Juan HU, Fan LIU, Bing XIAO, Ya–Bei ZUO, Wei CUI. C-reactive protein aggravates myocardial ischemia/reperfusion injury through activation of extracellular-signal-regulated kinase 1/2. J Geriatr Cardiol 2018; 15(7): 492-503. doi: 10.11909/j.issn.1671-5411.2018.07.001
Citation: Wei–Na PEI, Hai–Juan HU, Fan LIU, Bing XIAO, Ya–Bei ZUO, Wei CUI. C-reactive protein aggravates myocardial ischemia/reperfusion injury through activation of extracellular-signal-regulated kinase 1/2. J Geriatr Cardiol 2018; 15(7): 492-503. doi: 10.11909/j.issn.1671-5411.2018.07.001

C-reactive protein aggravates myocardial ischemia/reperfusion injury through activation of extracellular-signal-regulated kinase 1/2

doi: 10.11909/j.issn.1671-5411.2018.07.001
Funds:

The study was supported partly by the Health Department of Hebei Province Key Science and Technology Research program (20140073, Shijiazhuang, China) and the Science Research Foundation of the Second Hospital of Hebei Medical University (2h2201514, Shijiazhuang, China).

  • Received Date: 2018-05-26
  • Rev Recd Date: 2018-05-26
  • Publish Date: 2018-07-28
  • Background Ischemia/reperfusion injury (IRI) is an inflammatory response that occurs when tissue is reperfused following a prolonged period of ischemia. Several studies have indicated that C-reactive protein (CRP) might play an important role in inducing IRI. However, the effects of CRP on myocardial IRI and the underlying mechanisms have not been fully elucidated. This study aimed to investigate the association between CRP and myocardial IRI and the underlying mechanisms. Methods We simulated ischemia/reperfusion using oxygen-glucose deprivation/ reoxygenation (OGD/R) in neonatal Sprague-Dawley rat cardiomyocytes; reperfusion injury was induced by three hours of hypoxia with glucose and serum deprivation followed by one hour of reperfusion. Cell viability was tested with MTS assays, and cardiomyocyte damage was evaluated by lactate dehydrogenase (LDH) leakage. Mitochondrial membrane potential was measured using tetramethylrhodamine ethyl ester (TMRE) and mitochondrial permeability transition pore (mPTP) opening was measured using calcein/AM; both TMRE and caocein/AM were visualized with laser scanning confocal microscopy. In addition, we studied the signaling pathways underlying CRP-mediated ischemia/reperfusion injury via Western blot analysis. Results Compared with the simple OGD/R group, after intervention with 10 μg/mL CRP, cell viability decreased markedly (82.36 % ± 6.18% vs. 64.84% ± 4.06%, P = 0.0007), and the LDH leakage significantly increased (145.3 U/L ± 16.06 U/L vs. 208.2 U/L ± 19.23 U/L, P = 0.0122). CRP also activated mPTP opening and reduced mitochondrial membrane potential during myocardial ischemia/reperfusion. Pretreatment with 1 μM atorvastatin (Ator) before CRP intervention protected cardiomyocytes from IRI. Mitochondrial KATP channel opener diazoxide and mPTP inhibitor cyclosporin A also offset the effects of CRP in this process. The level of phosphorylated extracellular-signal-regulated kinase (ERK) 1/2 was significantly higher after pre-treatment with CRP compared with the OGD/R group (170.4% ± 3.00% vs. 93.53% ± 1.94%, P vs. 122.7% ± 5.30%, P = 0.0003) and ERK 1/2 phosphorylation significantly reduced after co-treatment with Ator and CRP compared with the level after CRP pretreatment alone. Conclusions Our results suggested that CRP directly aggravates myocardial IRI in myocardial cells and that this effect is primarily mediated by inhibiting mitochondrial ATP- sensitive potassium (mitoKATP) channels and promoting mPTP opening. Ator counteracts these effects and can reduce CRP-induced IRI. One of the mechanisms of CRP-induced IRI may be related to the sustained activation of the ERK signaling pathway.
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