A cardioprotective role for platelet-activating factor through NOS-dependent S-nitrosylation.
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.
Leary
Peter J
PJ
Division of Critical Care Medicine, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA.
Rajasekaran
Surender
S
Morrison
R Ray
RR
Tuomanen
Elaine I
EI
Chin
Thomas K
TK
Hofmann
Polly A
PA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D048430:Cell Shape; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D046934:Ginkgolides / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism*; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D016277:Ventricular Function, Left
D004791:Enzyme Inhibitors; D046934:Ginkgolides; D007783:Lactones; D009124:Muscle Proteins; D010972:Platelet Activating Factor; D019335:Nitroarginine; D009569:Nitric Oxide; C045856:ginkgolide B; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D002118:Calcium