Submitted on August 21, 2008
Revised on March 27, 2009
Accepted on March 27, 2009
Redox-sensitive Akt and Src Regulate Coronary Collateral Growth in the Metabolic Syndrome
Ryan E Reed1, Barry Potter2, Erika Smith3, Rashmi Jadhav3, Patricia Villalta3, Hanjoong Jo4, and Petra Rocic5*
1 Louisiana State University Health Sciences Center
2 LSUHSC
3 University of South Alabama
4 Emory University, Georgia Tech
5 University of South Alabama, College of Medicine
* To whom correspondence should be addressed. E-mail: procic{at}usouthal.edu.
We have recently shown that the inability of repetitive ischemia (RI) to activate p38 MAPK (p38) and Akt in metabolic syndrome (JCR) rats was associated with impaired coronary collateral growth (CCG). Furthermore, Akt and p38 activation correlated with optimal O2·- levels and was altered in JCR, and redox-sensitive p38 activation was required for CCG. Here we determined whether activation of Src, a possible upstream regulator, was altered in JCR, and whether redox-dependent Src and Akt activation were required for CCG. CCG was assessed by myocardial blood flow (microspheres), and kinase activation by Western blot, in the normal (NZ) and collateral-dependent (CZ) zones. RI induced Src activation (~3 fold) in healthy (WKY) but not in JCR animals. Akt inhibition decreased (~50%), and Src inhibition blocked RI-induced CCG in WKY. Src inhibition decreased p38 and Akt activation. Myocardial oxidative stress (O2·-, oxidized/reduced thiols) was measured quantitatively (X-band EPR). An antioxidant, apocynin, reduced RI-induced oxidative stress in JCR to levels induced by RI in WKY vs. reduction in WKY to very low levels. This resulted in significant restoration of p38 (~80%), Akt (~65%) and Src (~90%) activation in JCR, but decreased activation in WKY (p38~45%, Akt~65%, Src~100%) correlating with reduced CZ flow in WKY (~70%), but significantly restored CZ flow in JCR (~75%). We conclude: 1) Akt and Src are required for CCG, 2) Src is a redox-sensitive upstream regulator of RI-induced p38 and Akt activation, and 3) optimal oxidative stress levels are required for RI-induced p38, Akt and Src activation and CCG.
