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

Peter J. Leary, Surender Rajasekaran, R. Ray Morrison, Elaine I. Tuomanen, Thomas K. Chin, Polly A. Hofmann

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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 Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)H2775-H2784
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number6
DOIs
StatePublished - Jun 1 2008

Fingerprint

Platelet Activating Factor
Muscle Cells
Nitric Oxide
Heart Injuries
Inflammation Mediators
platelet activating factor receptor
Knockout Mice
Reperfusion
Phospholipids
Proteins
Ischemia
Perfusion

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Leary, Peter J. ; Rajasekaran, Surender ; Morrison, R. Ray ; Tuomanen, Elaine I. ; Chin, Thomas K. ; Hofmann, Polly A. / A cardioprotective role for platelet-activating factor through NOS-dependent S-nitrosylation. In: American Journal of Physiology - Heart and Circulatory Physiology. 2008 ; Vol. 294, No. 6. pp. H2775-H2784.
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A cardioprotective role for platelet-activating factor through NOS-dependent S-nitrosylation. / Leary, Peter J.; Rajasekaran, Surender; Morrison, R. Ray; Tuomanen, Elaine I.; Chin, Thomas K.; Hofmann, Polly A.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 294, No. 6, 01.06.2008, p. H2775-H2784.

Research output: Contribution to journalArticle

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AU - Rajasekaran, Surender

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