Increased neuronal nitric oxide synthase-derived NO production in the failing human heart.
Experimental data suggest that nitric oxide (NO) generated from neuronal NO synthase (nNOS) modulates the myocardial inotropic state. To assess the contribution of NO, derived from endothelial and neuronal isoforms, to the pathophysiology of congestive heart failure in human beings, we compared expression, localisation, and specific activity of NOS isoforms in myocardium from patients with dilated cardiomyopathy with those in controls who had died from head trauma or intracranial bleeds. Diseased hearts had a significant increase in nNOS mRNA and protein expression, and activity associated with the translocation of nNOS to the sarcolemma through interactions with caveolin 3. Enhanced nNOS activity counteracted a decrease in eNOS expression and activity. Our results provide evidence of increased nNOS-derived NO in the failing human heart. Such altered regulation may be important in the pathophysiology of cardiac dysfunction in human congestive heart failure.
Damy
Thibaud
T
INSERM U572 Hôpital Lariboisière, IFR J Marrey Paris-7, 41 Boulevard de la Chapelle, 75475 Paris Cedex 10, Université D Diderot, Paris, France.
Ratajczak
Philippe
P
Shah
Ajay M
AM
Camors
Emmanuel
E
Marty
Isabelle
I
Hasenfuss
Gerd
G
Marotte
Françoise
F
Samuel
Jane-Lise
JL
Heymes
Christophe
C
D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D051244:Caveolin 3; D022461:Caveolins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism
C417736:CAV3 protein, human; D051244:Caveolin 3; D022461:Caveolins; D018841:HSP90 Heat-Shock Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D009569:Nitric Oxide; C496320:NOS1 protein, human; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D002118:Calcium