Signaling pathways of a structural analogue of apelin-12 involved in myocardial protection against ischemia/reperfusion injury.
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 С (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.
Russian Cardiology Research-and-Production Complex, 3rd Cherepkovskaya Str., 15A, 121552 Moscow, Russian Federation. Electronic address: olpi@cardio.ru.
Oleg I
OI
Pisarenko
Russian Cardiology Research-and-Production Complex, 3rd Cherepkovskaya Str., 15A, 121552 Moscow, Russian Federation. Electronic address: vss-43@mail.ru.
Valentin S
VS
Shulzhenko
Russian Cardiology Research-and-Production Complex, 3rd Cherepkovskaya Str., 15A, 121552 Moscow, Russian Federation. Electronic address: i.studneva@cardio.ru.
Irina M
IM
Studneva
Russian Cardiology Research-and-Production Complex, 3rd Cherepkovskaya Str., 15A, 121552 Moscow, Russian Federation. Electronic address: serebrolar@yandex.ru.
Larisa I
LI
Serebryakova
Russian Cardiology Research-and-Production Complex, 3rd Cherepkovskaya Str., 15A, 121552 Moscow, Russian Federation. Electronic address: newera@yandex.ru.
Yulia A
YA
Pelogeykina
Russian Cardiology Research-and-Production Complex, 3rd Cherepkovskaya Str., 15A, 121552 Moscow, Russian Federation. Electronic address: oxanamma@mail.ru.
Oxana M
OM
Veselova
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D036341:Intercellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D017382:Reactive Oxygen Species; C495200:apelin-12 peptide
Cardioprotection; Ischemia/reperfusion injury; Signal transduction; Structural analogue of apelin-12