title: Inducible nitric oxide synthase deficiency protects the heart from systolic overload-induced ventricular hypertrophy and congestive heart failure.
abstract: Inducible nitric oxide synthase (iNOS) protein is expressed in cardiac myocytes of patients and experimental animals with congestive heart failure (CHF). Here we show that iNOS expression plays a role in pressure overload-induced myocardial chamber dilation and hypertrophy. In wild-type mice, chronic transverse aortic constriction (TAC) resulted in myocardial iNOS expression, cardiac hypertrophy, ventricular dilation and dysfunction, and fibrosis, whereas iNOS-deficient mice displayed much less hypertrophy, dilation, fibrosis, and dysfunction. Consistent with these findings, TAC resulted in marked increases of myocardial atrial natriuretic peptide 4-hydroxy-2-nonenal (a marker of lipid peroxidation) and nitrotyrosine (a marker for peroxynitrite) in wild-type mice but not in iNOS-deficient mice. In response to TAC, myocardial endothelial NO synthase and iNOS was expressed as both monomer and dimer in wild-type mice, and this was associated with increased reactive oxygen species production, suggesting that iNOS monomer was a source for the increased oxidative stress. Moreover, systolic overload-induced Akt, mammalian target of rapamycin, and ribosomal protein S6 activation was significantly attenuated in iNOS-deficient mice. Furthermore, selective iNOS inhibition with 1400W (6 mg/kg per hour) significantly attenuated TAC induced myocardial hypertrophy and pulmonary congestion. These data implicate iNOS in the maladaptative response to systolic overload and suggest that selective iNOS inhibition or attenuation of iNOS monomer content might be effective for treatment of systolic overload-induced cardiac dysfunction.
authors.affiliation: Center of Vascular Biology and Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.forename: Elza D
authors.initials: ED
authors.lastname: van Deel
authors.forename: Guangshuo
authors.initials: G
authors.lastname: Zhu
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001018:Aortic Diseases / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001596:Benzylamines / Q000494:pharmacology; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control*; D002908:Chronic Disease; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology / Q000517:prevention & control*; D006973:Hypertension / Q000201:enzymology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013599:Systole; D058570:TOR Serine-Threonine Kinases; D014661:Vasoconstriction
chemical_list: D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D017382:Reactive Oxygen Species; D038601:Ribosomal Protein S6; D009320:Atrial Natriuretic Factor; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011494:Protein Kinases; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020778:Matrix Metalloproteinase 2