Myocardial protection by N,N,N-trimethylsphingosine in ischemia reperfusion injury is mediated by inhibition of P-selectin
| Autor: | Toyoaki Murohara, Allan M. Lefer, Tareck O. Nossuli, John A. Delyani, Rosario Scalia |
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| Rok vydání: | 1996 |
| Předmět: |
Blood Platelets
Male P-selectin Neutrophils Immunology Myocardial Infarction Ischemia Biology Pharmacology Rats Sprague-Dawley Sphingosine In vivo medicine Animals Immunology and Allergy Creatine Kinase Protein kinase C Peroxidase Microcirculation Myocardium Cell Biology medicine.disease Rats P-Selectin Reperfusion Injury biology.protein Platelet aggregation inhibitor Creatine kinase Endothelium Vascular Reperfusion injury Platelet Aggregation Inhibitors Intravital microscopy |
| Zdroj: | Journal of Leukocyte Biology. 59:317-324 |
| ISSN: | 1938-3673 0741-5400 |
| Popis: | 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 NG-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. |
| Databáze: | OpenAIRE |
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