ERK-MAPK signaling opposes rho-kinase to reduce cardiomyocyte apoptosis in heart ischemic preconditioning

Mol Med. Jul-Aug 2010;16(7-8):307-15. doi: 10.2119/molmed.2009.00121. Epub 2010 Mar 17.

Abstract

We and others have reported that Rho-kinase plays an important role in the pathogenesis of heart ischemia/reperfusion (I/R) injury. Studies have also demonstrated that the activation of Rho-kinase is reversed in ischemic preconditioning (IPC). However, the mechanisms by which Rho-kinase is increased in I/R and reversed in IPC are not thoroughly understood. In female Wistar rats, we created I/R by ligating the left anterior-descending branch of the coronary artery (LAD) for 30 min and releasing the ligature for 180 min. IPC rats underwent IPC (two cycles of 5-min ligation of the LAD and 5-min reflow) before I/R. IPC caused a significant increase in extracellular signal-regulated kinase (ERK)1/2 activity and reduced Rho-kinase activity and cardiomyocyte apoptosis (P<0.05 versus I/R). Administration of PD98059, an inhibitor of ERK-mitogen-activated protein kinase (MAPK), increased cardiomyocyte apoptosis, Caspase-3 activity and myocardial infarction size (P<0.05 versus IPC). Western-blot analysis showed that administration of PD98059 increased Rho-kinase activity. Treatment with fasudil, an inhibitor of Rho-kinase, reversed cell apoptosis caused by treatment with PD98059 in IPC. In addition, ROCK1 (Rho-kinase 1) may be the major Rho-kinase isoform that is opposed by ERK-MAPK signaling in IPC. These results indicate that ERK-MAPK signaling is required in IPC to oppose Rho-kinase activity in cardiomyocyte apoptosis in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Blotting, Western
  • Caspase 3 / metabolism
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Flavonoids / pharmacology
  • In Situ Nick-End Labeling
  • Ischemic Preconditioning, Myocardial
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / pathology
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / pathology
  • Myocardial Reperfusion Injury / prevention & control
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Rats
  • Rats, Wistar
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / genetics
  • rho-Associated Kinases / metabolism*
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Flavonoids
  • rho-Associated Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Caspase 3
  • rhoA GTP-Binding Protein
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one