AJP - Heart and Circulatory Physiology, Vol 269, Issue 2 504-H514, Copyright © 1995 by American Physiological Society

ARTICLES

Myocardial and endothelial protection by TMS in ischemia-reperfusion injury

T. Murohara, M. Buerke, J. Margiotta, F. Ruan, Y. Igarashi, S. Hakomori and A. M. Lefer
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

N,N,N-trimethylsphingosine (TMS), a stable synthetic sphingosine derivative, was investigated in a feline model of myocardial ischemia (90 min) and reperfusion (270 min) injury. TMS (60 micrograms/kg), administered intravenously 10 min before reperfusion, significantly attenuated myocardial necrosis (15 +/- 3 vs. 31 +/- 4% necrosis of area at risk, P < 0.01) and cardiac myeloperoxidase activities, a marker of neutrophil accumulation, compared with vehicle-treated cats. Endothelium-dependent relaxation to acetylcholine in ischemic-reperfused coronary artery rings treated with TMS was also significantly preserved compared with vehicle (73 +/- 4 vs. 34 +/- 4% vasorelaxation, P < 0.01). Polymorphonuclear neutrophil (PMN) adherence to coronary endothelium 270 min after reperfusion was markedly attenuated in the TMS group compared with vehicle-treated cats (37 +/- 5 vs. 76 +/- 5 PMN/mm2, P < 0.01). TMS also attenuated upregulation of P-selectin on coronary venular endothelium by immunohistochemistry. This was consistent with in vitro findings that TMS attenuates PMN adherence to thrombin-stimulated coronary endothelium and P-selectin upregulation on thrombin-stimulated cat platelets. A sphingolipid derivative, TMS at physiological concentrations exerts cardioprotective actions and preserves coronary endothelial function following myocardial ischemia and reperfusion in vivo. The effects appear to be mediated by the inhibition of PMN-endothelial interaction and subsequent accumulation into the ischemic myocardium. Thus TMS may be a useful agent in attenuating myocardial reperfusion injury.

This article has been cited by other articles:

				S. Gundewar, J. W. Calvert, J. W. Elrod, and D. J. Lefer Cytoprotective effects of N,N,N-trimethylsphingosine during ischemia- reperfusion injury are lost in the setting of obesity and diabetes Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2462 - H2471. [Abstract] [Full Text] [PDF]

				B. Yang, L. Graham, S. Dikalov, R. P. Mason, J. R. Falck, J. K. Liao, and D. C. Zeldin Overexpression of Cytochrome P450 CYP2J2 Protects against Hypoxia-Reoxygenation Injury in Cultured Bovine Aortic Endothelial Cells Mol. Pharmacol., August 1, 2001; 60(2): 310 - 320. [Abstract] [Full Text] [PDF]

				S. Chatterjee Sphingolipids in Atherosclerosis and Vascular Biology Arterioscler Thromb Vasc Biol, October 1, 1998; 18(10): 1523 - 1533. [Abstract] [Full Text] [PDF]

				T. Murohara, R. Scalia, and A. M. Lefer Lysophosphatidylcholine Promotes P-Selectin Expression in Platelets and Endothelial Cells : Possible Involvement of Protein Kinase C Activation and Its Inhibition by Nitric Oxide Donors Circ. Res., May 1, 1996; 78(5): 780 - 789. [Abstract] [Full Text]

				T. Murohara, S. J. Parkinson, S. A. Waldman, and A. M. Lefer Inhibition of Nitric Oxide Biosynthesis Promotes P-selectin Expression in Platelets : Role of Protein Kinase C Arterioscler Thromb Vasc Biol, November 1, 1995; 15(11): 2068 - 2075. [Abstract] [Full Text]