Cardiomyocyte-specific overexpression of an active form of rac predisposes the heart to increased myocardial stunning and ischemia-reperfusion injury

M. A. Hassan Talukder, Mohammad T. Elnakish, Fuchun Yang, Yoshinori Nishijima, Mazin A. Alhaj, Murugesan Velayutham, Hamdy H. Hassanain, Jay L. Zweier

Research output: Contribution to journalArticle

Abstract

The GTPbinding protein Rac regulates diverse cellular functions including activation of NADPH oxidase, a major source of superoxide production (O2 ·-). Rac1-mediated NADPH oxidase activation is increased after myocardial infarction (MI) and heart failure both in animals and humans; however, the impact of increased myocardial Rac on impending ischemia-reperfusion (I/R) is unknown. A novel transgenic mouse model with cardiac-specific overexpression of constitutively active mutant form of Zea maize Rac D (ZmRacD) gene has been reported with increased myocardial Rac-GTPase activity and O2·- generation. The goal of the present study was to determine signaling pathways related to increased myocardial ZmRacD and to what extent hearts with increased ZmRacD proteins are susceptible to I/R injury. The effect of myocardial I/R was examined in young adult wild-type (WT) and ZmRacD transgenic (TG) mice. In vitro reversible myocardial I/R for postischemic cardiac function and in vivo regional myocardial I/R for MI were performed. Following 20-min global ischemia and 45-min reperfusion, postischemic cardiac contractile function and heart rate were significantly reduced in TG hearts compared with WT hearts. Importantly, acute regional myocardial I/R (30-min ischemia and 24-h reperfusion) caused significantly larger MI in TG mice compared with WT mice. Western blot analysis of cardiac homogenates revealed that increased myocardial ZmRacD gene expression is associated with concomitant increased levels of NADPH oxidase subunit gp91phox, O2·-, and P21-activated kinase. Thus these findings provide direct evidence that increased levels of active myocardial Rac renders the heart susceptible to increased postischemic contractile dysfunction and MI following acute I/R.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number2
DOIs
StatePublished - Jan 15 2013
Externally publishedYes

Keywords

  • Cardiac function
  • Infarction
  • Ischemia-reperfusion
  • Zmracd expression

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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