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.