Pharmacological postconditioning treatment of myocardial infarction with netrin-1

Abstract

The present study investigated whether pharmacological postconditoning with netrin-1 is cardioprotective against ischemia reperfusion (I/R) injury, and the underlying signaling mechanisms. Langendorff perfused hearts isolated from wild-type (WT) C57BL/6 or DCC+/- mice underwent a 20-min of ischemia, followed by a 60-min of reperfusion, in the presence or absence of netrin-1, or netrin-1 in combination with U0126 (MEK1/2 inhibitor), or PTIO (nitric oxide/NO scavenger). In WT mice, netrin-1 postconditioning dramatically reduced infarct size to 17.0±2.5%, from 40.5±4.2% in the untreated I/R group. U0126 or PTIO alone had no effect on infarct size but abolished the effects of netrin-1. The protective effect of netrin-1 was markedly diminished in DCC+/- mice (44.5±2% vs. 15±2.6% for infract size in DCC+/- vs. DCC+/+ group). Our results indicate that netrin-1, given as a pharmacological postconditioning agent, induces cardioprotection via a DCC-dependent mechanism that involves ERK1/2 activation and NO production. Combined with our previous findings, netrin-1 treatment proves to be extremely and consistently beneficial whenever delivered to the heart, establishing its substantial promises for being developed into a robust therapeutic strategy for acute myocardial infarction.