Endothelial dysfunction in chronic myocardial infarction despite increased vascular endothelial nitric oxide synthase and soluble guanylate cyclase expression: role of enhanced vascular superoxide production.
BACKGROUND
Endothelial dysfunction of the peripheral vasculature is a well-known phenomenon in congestive heart failure that contributes to the elevated peripheral resistance; however, the underlying mechanisms have not yet been clarified.


RESULTS
Dilator responses, the expression of protein and mRNA of the endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and soluble guanylate cyclase (sGC), and superoxide anion (O(2)(-)) and peroxynitrite production were determined in aortic rings from Wistar rats 8 weeks after myocardial infarction and compared with those in sham-operated animals. In rats with heart failure, the concentration-response curve of the endothelium-dependent vasodilator acetylcholine (after preconstriction with phenylephrine) was significantly shifted to the right, and the maximum relaxation was attenuated. Determination of expression levels of the 2 key enzymes for NO-mediated dilations, eNOS and sGC, revealed a marked upregulation of both enzymes in aortas from rats with heart failure, whereas iNOS expression was not changed. Pretreatment with exogenous superoxide dismutase partially restored the acetylcholine-induced relaxation in aortas from rats with heart failure. Aortic basal and NADH-stimulated O(2)(-) production assessed by use of lucigenin-enhanced chemiluminescence was significantly elevated in rats with chronic myocardial infarction. Peroxynitrite-mediated nitration of protein tyrosine residues was not different between the 2 groups of rats.


CONCLUSIONS
These results demonstrate that endothelial dysfunction in ischemic heart failure occurs despite an enhanced vascular eNOS and sGC expression and can be attributed to an increase in vascular O(2)(-) production by an NADH-dependent oxidase. By inactivation of NO, O(2)(-) production appears to be an essential mechanism for the endothelial dysfunction observed in heart failure.
II. Medizinische Klinik, Universitätsklinikum Mannheim, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, and Institut für Kardiovaskuläre Physiologie, Klinikum der J.W. Goethe-Universität, Frankfurt, Germany.
J
J
Bauersachs
A
A
Bouloumié
D
D
Fraccarollo
K
K
Hu
R
R
Busse
G
G
Ertl
D000109:Acetylcholine; D000818:Animals; D001013:Aorta, Thoracic; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006162:Guanylate Cyclase / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism; D009203:Myocardial Infarction / Q000097:blood / Q000378:metabolism*; D009566:Nitrates / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010656:Phenylephrine; D051381:Rats; D017208:Rats, Wistar; D012083:Renin / Q000097:blood; D013482:Superoxide Dismutase / Q000032:analysis / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*; D015854:Up-Regulation; D014665:Vasodilator Agents
D009566:Nitrates; D014665:Vasodilator Agents; D013481:Superoxides; D010656:Phenylephrine; C039642:peroxynitric acid; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D013482:Superoxide Dismutase; D012083:Renin; D006162:Guanylate Cyclase; D000109:Acetylcholine