title: Cyclooxygenase-2 in myocardium stimulation by angiotensin-II in cultured cardiac fibroblasts and role at acute myocardial infarction.
abstract: Myocardial infarction is followed by a complex repair process that includes a significant role for inflammatory cells. Cyclooxygenase-2 (COX-2) plays a key role in mediating inflammation. Contribution of COX-2 to inflammatory response following myocardial infarction is less certain. In an effort to evaluate the function of COX-2 and prostaglandin E(2)(PGE(2)) in myocardial infarction, we examined the role of COX-2 after angiotensin II (Ang II) stimulation in cardiac fibroblasts and in rats with experimental myocardial infarction (MI). We combined Western blot analysis and enzyme immunoassay to demonstrate COX-2 expression and PGE(2)release in cardiac fibroblasts. Isolated cardiac fibroblasts were stimulated with Ang II. Unstimulated fibroblasts showed no COX-2 protein expression. Fibroblasts stimulated with Ang II showed a strong time-dependent expression of COX-2 protein. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 but not the p42/44 MAPK-inhibitor PD98059 suppressed Ang II-induced COX-2 protein expression. COX-2 expression correlated with a significantly increased PGE(2)release from cardiac fibroblasts. The COX-2 specific inhibitor NS-398 suppressed the Ang II-stimulated PGE(2)production. We then investigated COX-2 expression and inflammatory cell infiltration in our rat model of myocardial infarction. MI was produced by coronary artery ligation in adult female Wistar rats. The period of coronary artery occlusion was 96 h. The selective COX-2 inhibitor rofecoxib (3 mg/kg/d), administered orally, was given one day before MI and continued for four days. Western blotting showed expression of COX-2 protein in the area of necrosis and the infarct border zone. Immunofluorescence analysis showed macrophage infiltration as well as fibroblast proliferation in the infarct border zone of 4-d infarcted tissue and a significantly reduced cell invasion and fibroblast proliferation in infarcted tissue of rats treated with rofecoxib. MI size at day 4 was comparable in untreated and treated rats. In conclusion, we demonstrate that pharmacological interference with prostaglandin synthesis in myocardial infarction is associated with reduced myocardial invasion of inflammatory cells.
authors.affiliation: Department of Medicine, University of Würzburg, Würzburg, Germany. N.Scheuren@medizin.uni-wuerzburg.de
authors.forename: Nicole
authors.initials: N
authors.lastname: Scheuren
authors.forename: Martina
authors.initials: M
authors.lastname: Jacobs
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Winfried
authors.initials: W
authors.lastname: Schorb
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004527:Egg Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism*; D007783:Lactones / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism*; D009336:Necrosis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D013450:Sulfones; D013997:Time Factors; D014746:Vimentin / Q000096:biosynthesis; D000072216:Zona Pellucida Glycoproteins; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D004527:Egg Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007527:Isoenzymes; D007783:Lactones; D008562:Membrane Glycoproteins; D011453:Prostaglandins; D011725:Pyridines; D011956:Receptors, Cell Surface; D013450:Sulfones; D014746:Vimentin; D000072216:Zona Pellucida Glycoproteins; C116926:rofecoxib; D000804:Angiotensin II; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one