Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction.
Using inducible nitric oxide (NO) synthase (iNOS) knockout mice (iNOS-/-), we tested the hypotheses that 1) lack of iNOS attenuates cardiac remodeling and dysfunction and improves cardiac reserve postmyocardial infarction (MI), an effect that is partially mediated by reduction of oxidative stress due to reduced interaction between NO and reactive oxygen species (ROS); and 2) the cardioprotection afforded by iNOS deletion is eliminated by Nomega-nitro-L-arginine methyl ester (L-NAME) due to inhibition of endothelial NOS (eNOS) and neuronal NOS (nNOS). MI was induced by ligating the left anterior descending coronary artery. Male iNOS-/- mice and wild-type controls (WT, C57BL/6J) were divided into sham MI, MI+vehicle, and MI+l-NAME (100 mg.kg(-1).day(-1) in drinking water for 8 wk). Cardiac function was evaluated by echocardiography. Left ventricular (LV) maximum rate of rise of ventricular pressure divided by pressure at the moment such maximum occurs (dP/dt/instant pressure) in response to isoproterenol (100 ng.kg(-1).min(-1) iv) was measured with a Millar catheter. Collagen deposition, myocyte cross-sectional area, and expression of nitrotyrosine and 4-hydroxy-2-nonenal (4-HNE), markers for ROS, were determined by histopathological and immunohistochemical staining. We found that the MI-induced increase in LV chamber dimension and the decrease in ejection fraction, an index of systolic function, were less severe in iNOS-/- compared with WT mice. L-NAME worsened LV remodeling and dysfunction further, and these detrimental effects were also attenuated in iNOS-/- mice, associated with better preservation of cardiac function. Lack of iNOS also reduced nitrotyrosine and 4-HNE expression after MI, indicating reduced oxidative stress. We conclude that iNOS does not seem to be a pathological mediator of heart failure; however, the lack of iNOS improves cardiac reserve post-MI, particularly when constitutive NOS isoforms are blocked. Decreased oxidative stress and other adaptive mechanisms independent of NOS may be partially responsible for such an effect, which needs to be studied further.
Liu
Yun-He
YH
Hypertension and Vascular Research Div., Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202-2689, USA.
Carretero
Oscar A
OA
Cingolani
Oscar H
OH
Liao
Tang-Dong
TD
Sun
Ying
Y
Xu
Jiang
J
Li
Lisa Y
LY
Pagano
Patrick J
PJ
Yang
James J
JJ
Yang
Xiao-Ping
XP
D000818:Animals; D001794:Blood Pressure; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D013318:Stroke Volume; D015996:Survival Rate; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology*; D020257:Ventricular Remodeling / Q000502:physiology*
D052247:Nitric Oxide Synthase Type II