Increased expression of constitutive nitric oxide synthase III,but not inducible nitric oxide synthase II,in human heart failure

Objectives. The purpose of the present study was to examine the expression of the endothelial-type nitric oxide synthase (NOS III) and the inducible-type NOS (NOS II) in human myocardium and their regulation in heart failure from patients with different etiologies.Background. In heart failure, plasma levels of nitrates were found to be elevated. However, data on myocardial NOS expression in heart failure are conflicting.Methods. Using RNase protection analysis and Western blotting, the expression of NOS III and NOS II was investigated in ventricular myocardium from nonfailing (NF) hearts (n = 5) and from failing hearts of patients with idiopathic dilated cardiomyopathy (dCMP, n = 14), ischemic cardiomyopathy (iCMP, n = 9) or postmyocarditis cardiomyopathy (mCMP, n = 7). Furthermore, immunohistochemical studies were performed to localize NOS III and NOS II within the ventricular myocardium.Results. In failing human hearts, NOS III mRNA levels were increased to 180% in dCMP, 200% in iCMP and to 210% in mCMP as compared to NF hearts. Similarly, in Western blots (using constitutively expressed beta-tubulin as a reference) NOS III protein expression was increased about twofold in failing compared to NF hearts. Immunohistochemical studies with a selective antibody to NOS III showed no obvious differences in the staining of the endothelium of cardiac blood vessels from NF and failing human hearts. However, NOS III-immunoreactivity in cardiomyocytes was significantly more intense in failing compared to NF hearts. Low expression of NOS II mRNA was detected in only 2 of 30 failing human hearts and was not found in NF hearts. Inducible-type NOS protein was undetectable in either group.Conclusions. We conclude that the increased NOS III expression in the ventricular myocardium of failing human hearts may contribute to the contractile dysfunction observed in heart failure and/or may play a role in morphologic alterations such as hypertrophy and apoptosis of cardiomyocytes.