Molecular mechanisms underlying netrin‐1 postconditioning induced cardioprotection against ischemia‐reperfusion injury

Abstract

Given as a preconditioning mimetic, we have recently shown that netrin‐1 markedly reduces myocardial injury after I/R. Here, we aimed to investigate whether and how netrin‐1, exerts cardioprotection in vivo when given postconditionally. This is considered more clinically relevant. Eight‐weeks old DCC+/+ wild type mice and mice deficient in netrin‐1 receptor DCC (DCC+/−) were subjected to 30 min of myocardial ischemia and 10 min (analysis of signaling pathways and free radical production) or 24 h of reperfusion (analysis of infarct size). In DCC +/+ mice, treatment with 5 μg/kg netrin‐1 at the onset of reperfusion most significantly reduced infarct size, Ca2+‐induced mitochondrial swelling and superoxide production comparing to other dosages used (1, 10, 50 μg/kg), while it increased NO bioavailability and activation of cardioprotective proteins (ERK1/2, p70S6K, eNOS). All of these beneficial effects were abolished in DCC +/− mice, or under conditions of co‐treatment with UO126 (MEK inhibitor) or PTIO (NO scavenger). These seem to be consistent with our earlier ex vivo observations to examine a postconditioning effect of netrin‐1 (published abstract). Therefore the present study strongly suggests that netrin‐1 can function as a postconditioning mimetic to protect the heart against I/R injury, via a ERK1/2/eNOS pathway that also involves activation of DCC.