title: Microsomal Prostaglandin E Synthase-1 Expression by Aortic Smooth Muscle Cells Attenuates the Differentiated Phenotype.
abstract: The development of numerous types of cardiovascular disease is associated with alteration of the vascular smooth muscle cell (SMC) phenotype. We have previously shown that abdominal aortic aneurysm progression in a mouse model of the disease is associated with reduced differentiation of SMCs within the lesion and that cyclooxygenase-2 (COX-2) is critical to initiation and progression of the aneurysms. The current studies used human aortic SMC (hASMC) cultures to better characterize mechanisms responsible for COX-2-dependent modulation of the SMC phenotype. Depending on the culture conditions, hASMCs expressed multiple characteristics of a differentiated and contractile phenotype, or a dedifferentiated and secretory phenotype. The pharmacological inhibition of COX-2 promoted the differentiated phenotype, whereas treatment with the COX-2-derived metabolite prostaglandin E2 (PGE2) increased characteristics of the dedifferentiated phenotype. Furthermore, pharmacological inhibition or siRNA-mediated knockdown of microsomal prostaglandin E synthase-1 (mPGES-1), the enzyme that functions downstream of COX-2 during the synthesis of PGE2, significantly increased expression of characteristics of the differentiated SMC phenotype. Therefore, our findings suggest that COX-2 and mPGES-1-dependent synthesis of PGE2 contributes to a dedifferentiated hASMC phenotype and that mPGES-1 may provide a novel pharmacological target for treatment of cardiovascular diseases where altered SMC differentiation has a causative role.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY.
authors.forename: Oreoluwa O
authors.initials: OO
authors.lastname: Adedoyin
authors.forename: Charles D
authors.initials: CD
authors.lastname: Loftin
mesh_terms: D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D010641:Phenotype; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone