Published online before print September 20, 2007, doi: 10.1161/CIRCRESAHA.107.159053
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Submitted on April 18, 2007
Revised on August 31, 2007
Accepted on September 12, 2007
Role of Ca2+-Independent Phospholipase A2 and Store-Operated Pathway in Urocortin-Induced Vasodilatation of Rat Coronary Artery
Tarik Smani *;
From the Laboratorio de Investigación Cardiovascular (T.S., A.D.-R., E.C.-S., A.O.), Hospital Universitario Virgen del Roció, Universidad de Sevilla, and Centro Andaluz de Biología Molecular & Medicina Regenerativa (A.H., A.H.-L.), Sevilla, Spain.
* To whom correspondence should be addressed. E-mail: tasmani{at}us.es.
Urocortin has been shown to produce vasodilatation in several arteries, but the precise mechanism of its action is still poorly understood. Here we demonstrate the role of store operated Ca2+ entry (SOCE) regulated by Ca2+-independent phospholipase A2 (iPLA2) in phenylephrine hydrochloride (PE)-induced vasoconstriction, and we present the first evidence that urocortin induces relaxation by the modulation of SOCE and iPLA2 in rat coronary artery. Urocortin produces an endothelium independent relaxation, and its effect is concentration-dependent (IC50
4.5 nmol/L). We show in coronary smooth muscle cells (SMCs) that urocortin inhibits iPLA2 activation, a crucial step for SOC channel activation, and prevents Ca2+ influx evoked by the emptying of the stores via a cAMP and protein kinase A (PKA)–dependent mechanism. Lysophophatidylcholine and lysophosphatidylinositol, products of iPLA2, exactly mimic the effect of the depletion of the stores in presence of urocortin. Furthermore, we report that long treatment with urocortin downregulates iPLA2 mRNA and proteins expression in rat coronary smooth muscle cells. In summary, we propose a new mechanism of vasodilatation by urocortin which involves the regulation of iPLA2 and SOCE via the stimulation of a cAMP/PKA-dependent signal transduction cascade in rat coronary artery.
Key words: urocortin • iPLA2 • vasoconstriction • store operated Ca2+ entry • cAMP-PKA
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