Inhibition of the activity of Rho-kinase reduces cardiomyocyte apoptosis in heart ischemia/reperfusion via suppressing JNK-mediated AIF translocation

Clin Chim Acta. 2009 Mar;401(1-2):76-80. doi: 10.1016/j.cca.2008.11.016. Epub 2008 Nov 24.

Abstract

Background: Recent studies have demonstrated that Rho-kinase has been proposed to play an important role in the pathogenesis of heart ischemia/reperfusion (I/R) injury. However, the mechanism of Rho-kinase mediated cardiomyocyte apoptosis in I/R is still not thoroughly understood.

Method: Studies were performed with female Wistar rats.

Results: Ischemia followed by reperfusion caused a significant increase in Rho-kinase, c-Jun NH2-terminal kinase (JNK) and apoptosis-inducing factor (AIF) activity. Administration of fasudil, an inhibitor of Rho-kinase, decreased myocardial infarction size from 59.89+/-3.83% to 38.62+/-2.66% (P<0.05) and cell apoptosis from 32.78+/-5.1% to 17.05+/-4.2% (P<0.05). Western blot analysis showed that administration of fasudil reduced the activation of JNK and attenuated mitochondrial-nuclear translocation of AIF. Additionally, administration of SP600125, an inhibitor of JNK, attenuated mitochondrial-nuclear translocation of AIF.

Conclusion: The inhibition of Rho-kinase reduced cell apoptosis in I/R in vivo via suppression of JNK-mediated AIF translocation.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Animals
  • Anthracenes / pharmacology
  • Apoptosis
  • Apoptosis Inducing Factor / drug effects
  • Apoptosis Inducing Factor / metabolism*
  • Female
  • MAP Kinase Kinase 4 / drug effects
  • MAP Kinase Kinase 4 / metabolism*
  • Myocardial Infarction / enzymology*
  • Myocardial Infarction / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / enzymology*
  • Reperfusion Injury / pathology
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism*

Substances

  • Aifm1 protein, rat
  • Anthracenes
  • Apoptosis Inducing Factor
  • Protein Kinase Inhibitors
  • pyrazolanthrone
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • rho-Associated Kinases
  • MAP Kinase Kinase 4
  • fasudil