NO and PGI(2) in coronary endothelial dysfunction in transgenic mice with dilated cardiomyopathy.
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.
Drelicharz
Lukasz
L
Dept. of Experimental Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, Krakow, 31-531, Poland.
Kozlovski
Valery
V
Skorka
Tomasz
T
Heinze-Paluchowska
Sylwia
S
Jasinski
Andrzej
A
Gebska
Anna
A
Guzik
Tomasz
T
Olszanecki
Rafal
R
Wojnar
Leszek
L
Mende
Ulrike
U
Csanyi
Gabor
G
Chlopicki
Stefan
S
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
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