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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/H2775    most recent 00269.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Leary, P. J. Articles by Hofmann, P. A. PubMed PubMed Citation Articles by Leary, P. J. Articles by Hofmann, P. A.

A cardioprotective role for platelet-activating factor through NOS-dependent S-nitrosylation

¹Division of Critical Care Medicine and ²Department of Infectious Diseases, St. Jude Children's Research Hospital, and Departments of ³Pediatrics and ⁴Physiology, University of Tennessee Health Sciences Center, Memphis, Tennessee

Submitted 12 March 2008 ; accepted in final form 18 April 2008

Controversy exists as to whether platelet-activating factor (PAF), a potent phospholipid mediator of inflammation, can actually protect the heart from postischemic injury. To determine whether endogenous activation of the PAF receptor is cardioprotective, we examined postischemic functional recovery in isolated hearts from wild-type and PAF receptor-knockout mice. Postischemic function was reduced in hearts with targeted deletion of the PAF receptor and in wild-type hearts treated with a PAF receptor antagonist. Furthermore, perfusion with picomolar concentrations of PAF improved postischemic function in hearts from wild-type mice. To elucidate the mechanism of a PAF-mediated cardioprotective effect, we employed a model of intracellular Ca²⁺ overload and loss of function in nonischemic ventricular myocytes. We found that PAF receptor activation attenuates the time-dependent loss of shortening and increases in intracellular Ca²⁺ transients in Ca²⁺-overloaded myocytes. These protective effects of PAF depend on nitric oxide, but not activation of cGMP. In addition, we found that reversible S-nitrosylation of myocardial proteins must occur in order for PAF to moderate Ca²⁺ overload and loss of myocyte function. Thus our data are consistent with the hypothesis that low-level PAF receptor activation initiates nitric oxide-induced S-nitrosylation of Ca²⁺-handling proteins, e.g., L-type Ca²⁺ channels, to attenuate Ca²⁺ overload during ischemia-reperfusion in the heart. Since inhibition of the PAF protective pathway reduces myocardial postischemic function, our results raise concern that clinical therapies for inflammatory diseases that lead to complete blockade of the PAF receptor may eliminate a significant, endogenous cardioprotective pathway.

cardioprotection; calcium handling; ischemia-reperfusion injury