Abstract 17337: Postconditioning with Netrin-1 Protects Against Myocardial Ischemia-Reperfusion Injury Via a DCC/ERK1/2/eNOS Mechanism
Given as a pre-conditioning mimetic, we have previously shown that netrin-1 markedly reduces myocardial ischemia-reperfusion (I/R) injury by increasing nitric oxyde (NO) bioavailability. However, its potential beneficial effect remains unknown if given as a post-conditioning agent. Langendorff perfused hearts isolated from C57BL/6 wild-type (WT) mice or DCC+/- mice underwent 20-min of global ischemia followed by 60-min of reperfusion (n=6). DCC (deleted in colorectal cancer) is one of the netrin-1 receptors we found to be however specifically involved in netrin-1 pre-conditioning induced cardioprotection. Netrin-1 was infused post-conditionally at the onset of reperfusion at 100 ng/mL concentration with and without UO126, a specific MEK1/2 inhibitor or 2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO), a NO-scavenger. In WT mice, netrin-1 postconditioning significantly reduced infarct size to 17±2.5% from 43.3±4.6% in the untreated control I/R group. This phenomenon is now further confirmed using an in vivo model of myocardial ischemic injury, 30-min coronary occlusion followed by 24-hr reperfusion. UO126 or PTIO administration alone had no effect on infarct size (respectively 44.8±3% and 39.8±1.7% vs 43.3±4.6% in the untreated control I/R group) but abolished the effects of netrin-1, implicating intermediate roles of MEK/ERK1/2 and NO (respectively 44.8±2% and 43.5±2.9% vs 17±2.5% in the netrin-1 treated I/R group). Indeed, ERK1/2 and eNOS phosphorylation was significantly upregulated by netrin-1 treatment. Interestingly, the protective effect of netrin-1 was markedly diminished in the DCC+/- mice (infarct size increased to 44.5±2% from 15±2.6 % in the DCC+/+ group), indicating a dependency on DCC of netrin-1 post-conditoning induced cardioprotection. Netrin-1 also feed-forwardly upregulated DCC protein expression. Taken together, these results strongly suggest that netrin-1 protects against I/R injury in the murine heart as a post-conditioning mimetic by increasing NO production via activation of a ERK1/2/eNOS pathway, which also involves DCC activation and upregulation. These findings demonstrate that netrin-1 can serve as an innovative and powerful agent for acute treatment of myocardial infarction.
- © 2011 by American Heart Association, Inc.