Role of Ca2+-independent phospholipase A2 and store-operated pathway in urocortin-induced vasodilatation of rat coronary artery.
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 approximately = 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.
Smani
Tarik
T
Laboratorio de Investigación Cardiovascular, Quirófanos Experimentales, Hospital General Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, E-41013 Sevilla, Spain. tasmani@us.es
Domínguez-Rodríguez
Alejandro
A
Hmadcha
Abdelkrim
A
Calderón-Sánchez
Eva
E
Horrillo-Ledesma
Angélica
A
Ordóñez
Antonio
A
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003331:Coronary Vessels / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D054512:Phospholipases A2, Calcium-Independent / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D054832:Urocortins / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects*
D054832:Urocortins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054512:Phospholipases A2, Calcium-Independent; D002118:Calcium