title: Deletion of inducible nitric oxide synthase provides cardioprotection in mice with 2-kidney, 1-clip hypertension.
abstract: Inducible NO synthase (iNOS) has been implicated in the pathogenesis of hypertension and target organ damage. We hypothesized that induction of iNOS contributes to left ventricular (LV) hypertrophy and dysfunction in mice with 2-kidney, 1-clip hypertension. Deletion of iNOS diminishes oxidative stress, thereby attenuating LV hypertrophy and enhancing cardiac performance. 2-Kidney, 1-clip hypertension was induced in mice lacking iNOS and wild-type controls (C57BL/6J). Sham-clipped mice served as controls. Systolic blood pressure was measured weekly by tail cuff. Left ventricular ejection fraction (by echocardiography) and cardiac response (maximum and minimum dP/dt, as well as an indicator of isovolumic contraction) to isoproterenol (50 ng per mouse, i.v.) were studied at the end of the experiment. 4-Hydroxy-2-nonenal (a byproduct of lipid peroxidation and an indicator of oxidative stress) was measured by immunohistochemical staining. gp91(phox), endothelial NO synthase, and iNOS protein expression were determined by Western blot. We found that systolic blood pressure, LV weight, myocyte cross-sectional area, interstitial collagen fraction, ejection fraction, and cardiac response to isoproterenol did not differ between strains with sham clipping. 2-Kidney, 1-clip hypertension increased systolic blood pressure, LV weight, myocyte cross-sectional area, and interstitial collagen fraction similarly in both strains. However, in mice lacking iNOS, maximum and minimum dP/dt, as well as an indicator of isovolumic contraction, markedly increased in response to isoproterenol, associated with decreased cardiac 4-hydroxy-2-nonenal expression and urinary nitrate/nitrite. We concluded that deletion of iNOS does not seem to play a significant role in preventing 2-kidney, 1-clip hypertension-induced hypertension and cardiac hypertrophy; however, it does enhance preservation of cardiac function, probably because of a reduction of iNOS-induced oxidative stress.
authors.affiliation: Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, Mich 48202-2689, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Sun
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Carretero
authors.forename: Jiang
authors.initials: J
authors.lastname: Xu
authors.forename: Nour-Eddine
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: James J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Pagano
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Yang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology; D017353:Gene Deletion; D006978:Hypertension, Renovascular / Q000150:complications / Q000209:etiology* / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D009566:Nitrates / Q000652:urine; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000502:physiology*; D009573:Nitrites / Q000652:urine; D009929:Organ Size / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012083:Renin / Q000097:blood; D013525:Surgical Instruments / Q000009:adverse effects
chemical_list: D009566:Nitrates; D009573:Nitrites; D017382:Reactive Oxygen Species; D052247:Nitric Oxide Synthase Type II; D012083:Renin