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

1 Division of Critical Care Medicine and 2 Department of Infectious Diseases, St. Jude Children's Research Hospital, and Departments of 3 Pediatrics and 4 Physiology, 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 Ca 2+ 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 Ca 2+ transients in Ca 2+ -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 Ca 2+ 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 Ca 2+ -handling proteins, e.g., L-type Ca 2+ channels, to attenuate Ca 2+ 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 Address for reprint requests and other correspondence: P. A. Hofmann, Dept. of Physiology, Univ. of Tennessee Health Science Center, 894 Union Ave., Memphis, TN 38163 (e-mail: phofmann{at}physio1.utmem.edu )