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

• Published in: Clinica chimica acta 2009-03, Vol.401 (1), p.76-80
• Main Authors: Zhang, Juan, Li, Xiao-Xing, Bian, Hong-Jun, Liu, Xiao-Bo, Ji, Xiao-Ping, Zhang, Yun
• Format: Article
• Language: English
• Subjects: 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; Apoptosis-inducing factor; c-Jun NH2-terminal kinase; Female; Heart I/R; 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; Rho-kinase
• ISSN: 0009-8981; 1873-3492
• DOI: 10.1016/j.cca.2008.11.016

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. Studies were performed with female Wistar rats. 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. The inhibition of Rho-kinase reduced cell apoptosis in I/R in vivo via suppression of JNK-mediated AIF translocation.