title: NO and PGI(2) in coronary endothelial dysfunction in transgenic mice with dilated cardiomyopathy.
abstract: OBJECTIVE
  The aim of the present work was to analyze coronary endothelial function in the transgenic mouse model of dilated cardiomyopathy (Tgalphaq*44 mice).
  
  
  METHODS
  Coronary vasodilatation, both NO-dependent (induced by bradykinin) and PGI(2)-dependent (induced by acetylcholine), was assessed in the isolated hearts of Tgalphaq*44 and FVB mice. Cardiac function was analyzed in vivo (MRI).
  
  
  RESULTS
  In Tgalphaq*44 mice at the age of 2-4 months cardiac function was preserved and there were no alterations in endothelial function. By contrast, in Tgalphaq*44 mice at the age of 14-16 months cardiac function was significantly impaired and NO, but not PGI(2)-dependent coronary function was altered. Interestingly, the basal level of PGI(2) in coronary circulation increased fourfold as compared to FVB mice. Cardiac O(2) (-) production increased 1.5-fold and 3-fold in Tgalphaq*44 vs. FVB mice at the age of 2-6 and 14-16 months, respectively, and was inhibited by apocynin. Interestingly, inhibition of NADPH oxidase or NOS-3 normalized augmented PGI(2) production in Tgalphaq*44 mice. There was also an increased expression of gp91phox in Tgalphaq*44 vs. FVB hearts, without evident alterations in the expression of COX-1, COX-2, NOS-3 and PGI(2)-synthase.
  
  
  CONCLUSIONS
  In the mouse model of dilated cardiomyopathy, endothelial dysfunction in coronary circulation is present in the late but not the early stage of heart failure pathology and is characterized by a decrease in NO bioavailability and a compensatory increase in PGI(2). Both the decrease in NO activity and the increase in PGI(2) activity may result from excessive O(2) (-) production by cardiac NADPH oxidase in Tgalphaq*44 hearts.
authors.affiliation: Dept. of Experimental Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, Krakow, 31-531, Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Drelicharz
authors.forename: Valery
authors.initials: V
authors.lastname: Kozlovski
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorka
authors.forename: Sylwia
authors.initials: S
authors.lastname: Heinze-Paluchowska
authors.forename: Andrzej
authors.initials: A
authors.lastname: Jasinski
authors.forename: Anna
authors.initials: A
authors.lastname: Gebska
authors.forename: Tomasz
authors.initials: T
authors.lastname: Guzik
authors.forename: Rafal
authors.initials: R
authors.lastname: Olszanecki
authors.forename: Leszek
authors.initials: L
authors.lastname: Wojnar
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mende
authors.forename: Gabor
authors.initials: G
authors.lastname: Csanyi
authors.forename: Stefan
authors.initials: S
authors.lastname: Chlopicki
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology
chemical_list: D008565:Membrane Proteins; D013481:Superoxides; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D019255:NADPH Oxidases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase