Exogenously administered chemically modified
apelin-12 (MA) has been shown to exhibit protective effects in
myocardial ischemia/reperfusion (I/R) injury. They include reduction of ROS formation, cell death and cardiometabolic abnormalities. The aim of the present study was to explore the role of the underlying signaling mechanisms involved in cardioprotection afforded by MA. Isolated perfused working rat hearts subjected to global
ischemia and anaesthetized rats in vivo exposed to LAD coronary artery occlusion were used.
Myocardial infarct size, cell membrane damage, cardiac dysfunction and metabolic state of the heart were used as indices of I/R injury at the end of reperfusion. Administration of specific inhibitors of MEK1/2, PI3K,
NO synthase (NOS) or the mitochondrial
ATP-sensitive K(+) (mito
KATP) channels (
UO126,
LY294002,
L-NAME or 5-hydroxydecanoate, respectively) reduced protective efficacy of MA in both models of I/R injury. This was evidenced by abrogation of
infarct size limitation, deterioration of cardiac function recovery, and attenuation of metabolic restoration and sarcolemmal integrity. An enhancement of functional and metabolic recovery in isolated reperfused hearts treated with MA was suppressed by
U-73122,
chelerythrine,
amiloride or
KB-R7943 (inhibitors of
phospholipase ะก (PLC),
protein kinase C (PKC), Na(+)/H(+) or Na(+)/Ca(2+) exchange, respectively). Additionally, co-infusion of MA with
amiloride or
L-NAME reduced the integrity of cell membranes at early reperfusion compared with the effect of
peptide alone. In conclusion, cardioprotection with MA is mediated by signaling via PLC and survival
kinases, PKC, PI3K, and MEK1/2, with activation of downstream targets, NOS and mito
KATP channels, and the sarcolemmal Na(+)/H(+) and Na(+)/Ca(2+) exchangers.