title: Substance P induces cardioprotection in ischemia-reperfusion via activation of AKT.
abstract: Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT.
authors.affiliation: Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina;
authors.forename: Shaiban
authors.initials: S
authors.lastname: Jubair
authors.affiliation: Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina;
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
authors.affiliation: Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Dehlin
authors.affiliation: Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Manteufel
authors.affiliation: Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Goldspink
authors.affiliation: Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Levick
authors.affiliation: Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina; Joseph.Janicki@uscmed.sc.edu.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Janicki
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015687:Cell Hypoxia; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D015398:Signal Transduction; D013373:Substance P / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002316:Cardiotonic Agents; D018040:Receptors, Neurokinin-1; D013373:Substance P; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT inhibitor; NK-1 receptor antagonist; apoptosis; isolated heart global ischemia and reperfusion; lactate dehydrogenase; left ventricular tissue slice culture