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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 14, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn346
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

EICOSANOID SIGNALING PATHWAYS IN THE HEART

Christopher M. Jenkins1, Ari Cedars1 and Richard W. Gross1,2,3

1 From the Division of Bioorganic Chemistry and Molecular Pharmacology, Departments of Medicine, Washington University School of Medicine, St. Louis, MO 63110
2 Departments of Molecular Biology & Pharmacology, Washington University School of Medicine, St. Louis, MO 63110
3 Department of Chemistry, Washington University, St. Louis, MO 63130

Address correspondence to: Richard W. Gross, Division of Bioorganic Chemistry and Molecular Pharmacology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8020, St. Louis, Missouri 63110; Tel. 314-362-2690; Fax. 314-362-1402; E-mail: rgross{at}wustl.edu

Myocardial phospholipids serve as primary reservoirs of arachidonic acid, which is liberated through the rate-determining hydrolytic action of cardiac phospholipases A2 (PLA2s). A predominant PLA2 in myocardium is calcium-independent phospholipase A2β (iPLA2β), which, through its calmodulin and ATP binding domains, is regulated by alterations in local cellular Ca2+ concentrations and cardiac bioenergetic status, respectively. Importantly, iPLA2β has been demonstrated to be activated by ischemia through elevation of the concentration of myocardial fatty acyl-CoA, which abrogates Ca2+/calmodulin-mediated inhibition of iPLA2β. Arachidonic acid released by PLA2-catalyzed hydrolysis of phospholipids serves as a precursor for eicosanoids generated by pathways dependent on cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP). Eicosanoids initiate and propagate diverse signaling cascades, primarily through their interaction with cellular receptors and ion channels. However, during pathologic states such as ischemia or congestive heart failure, eicosanoids contribute to multiple maladaptive changes including inflammation, alterations of cellular growth programs and activation of multiple transcriptional events leading to the deleterious sequelae of these pathologic states. This review summarizes the central roles of myocardial PLA2s in eicosanoid signaling in the heart, the major COX, LOX, and CYP pathways of eicosanoid generation in the myocardium, and the effects of important eicosanoids on receptor-, ion channel-, and transcription-mediated processes which facilitate cardiac hypertrophy, mediate ischemic preconditioning, and precipitate arrhythmogenesis in response to pathologic stimuli.

Time for primary review: 14 Days


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