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Myocardial protection by N,N,N ‐trimethylsphingosine in ischemia reperfusion injury is mediated by inhibition of P‐selectin
Author(s) -
Scalia Rosario,
Murohara Toyoaki,
Delyani John A.,
Nossuli Tareck O.,
Lefer Allan M.
Publication year - 1996
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.59.3.317
Subject(s) - intravital microscopy , reperfusion injury , myeloperoxidase , pharmacology , ischemia , p selectin , creatine kinase , endothelium , flow cytometry , biology , medicine , immunology , chemistry , platelet , endocrinology , inflammation , platelet activation , microcirculation
Abstract Polymorphonuclear leukocytes (PMNs) play an important role in myocardial ischemia/reperfusion (MI/R) injury. We examined the cardioprotective effects of N,N,N ‐trimethylsphingosine (TMS) in a murine model of MI (20 min) and R (24 h) injury in vivo, focusing on leukocyte‐endothelial interactions. TMS is a synthetic N‐methylated sphingosine derivative that has protein kinase C inhibitory activity and has been shown to prevent leukocyte activation. TMS (18 μg/kg), administered intravenously 1 min prior to reperfusion, significantly attenuated myocardial necrotic injury assessed by myocardial creatine kinase loss compared with MI/R rats receiving only vehicle ( P < 0.001). Cardiac myeloperoxidase activity, an index of PMN accumulation in the ischemic myocardium, was also significantly attenuated by TMS compared with rats receiving vehicle ( P < 0.001). We further examined whether TMS can attenuate leukocyte‐endothelial interaction by intravital microscopy. TMS significantly attenuated N G ‐nitro‐l‐arginine–methyl ester (l‐NAME)–stimulated PMN rolling and adherence to the rat microvascular endothelium. This action of TMS appears to be mediated by reduction of P‐selectin expression because immunohistochemical analysis demonstrated that TMS significantly attenuated endothelial P‐selectin expression in the l‐NAME‐superfused rat mesenteric microvasculature. Similarly, TMS markedly attenuated rapid P‐selectin expression in rat platelets stimulated with either thrombin or l‐NAME assessed by flow cytometry. In conclusion, TMS seems to be an effective cardioprotective agent by inhibiting early leukocyte‐endothelial interaction, thus preventing leukocyte accumulation in the ischemic reperfused myocardium.