Involvement of the Nicotinamide Adenosine Dinucleotide Phosphate Oxidase Isoform Nox2 in Cardiac Contractile Dysfunction Occurring in Response to Pressure Overload

• Published in: Journal of the American College of Cardiology 2006-02, Vol.47 (4), p.817-826
• Main Authors: Grieve, David J., Byrne, Jonathan A., Siva, Anjana, Layland, Joanne, Johar, Sofian, Cave, Alison C., Shah, Ajay M.
• Format: Article
• Language: English
• Subjects: Acetylcysteine - pharmacology; Animals; Aorta; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiomyocytes; Dehydrogenases; Echocardiography; Enzymes; Fibrosis; Heart failure; Heart rate; Hypertrophy, Left Ventricular - pathology; Hypertrophy, Left Ventricular - physiopathology; Isoenzymes - physiology; Kinases; Ligation; Male; Medical sciences; Mice; Mice, Knockout; Myocardial Contraction; Myocardium - cytology; Myocardium - pathology; NADPH Oxidases - physiology; Oxidative stress; Polymerase chain reaction; Rodents; Studies; Ventricular Function, Left
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2005.09.051

Involvement of the Nicotinamide Adenosine Dinucleotide Phosphate Oxidase Isoform Nox2 in Cardiac Contractile Dysfunction Occurring in Response to Pressure Overload David J. Grieve, Jonathan A. Byrne, Anjana Siva, Joanne Layland, Sofian Johar, Alison C. Cave, Ajay M. Shah Reactive oxygen species generated by the Nox2 nicotinamide adenosine dinucleotide phosphate oxidase are involved in angiotensin II-induced but not pressure-overload left ventricular hypertrophy (LVH). We studied the effect of Nox2 on contractile function. After aortic banding, Nox2−/−mice had significantly better contractile function than wild-type (WT) mice by echocardiography or LV pressure-volume analyses despite equivalent LVH. The antioxidant N-acetylcysteine normalized contractile function in banded WT. The Nox2−/−mice were protected against interstitial fibrosis after banding. These data indicate that the Nox2 oxidase contributes to cardiac contractile dysfunction and interstitial fibrosis after pressure overload, although it is not required for development of LVH. This study sought to examine the role of Nox2 in the contractile dysfunction associated with pressure-overload left ventricular hypertrophy (LVH). Reactive oxygen species (ROS) production is implicated in the pathophysiology of LVH. The nicotinamide adenosine dinucleotide phosphate oxidase isoform, Nox2, is pivotally involved in angiotensin II-induced hypertrophy but is not essential for development of pressure-overload LVH. Its possible impact on contractile function is unknown. The effects of aortic banding or sham surgery on cardiac contractile function and interstitial fibrosis were compared in adult Nox2−/−and matched wild-type (WT) mice. Banding induced similar increases in left ventricular (LV) mass in both groups. Banded Nox2−/−mice had better LV function than WT by echocardiography (e.g., fractional shortening 33.6 ± 2.5% vs. 21.4 ± 2.2%, p < 0.05). Comprehensive LV pressure-volume analyses also showed significant contractile dysfunction in banded WT compared with sham, whereas banded Nox2−/−mice had preserved function (e.g., maximum rate of rise of LV pressure: banded WT, 4,879 ± 213; vs. banded Nox2−/−, 5,913 ± 259 mm Hg/s; p < 0.05). Similar preservation of function was observed in isolated cardiomyocytes. The 24-h to 36-h treatment of banded WT mice with N-acetylcysteine resulted in recovery of contractile function. Cardiac interstitial fibrosis was significantly increased in banded WT but not Nox2−/−mice, to