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PRECLINICAL STUDY

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

King’s College London, Cardiovascular Division, Guy’s, King’s, and St. Thomas’ School of Medicine, London, England

Manuscript received January 1, 2005; revised manuscript received September 14, 2005, accepted September 19, 2005.

^_* Reprint requests and correspondence: Dr. Ajay M. Shah, Department of Cardiology, GKT School of Medicine, Bessemer Road, London SE5 9PJ England (Email: ajay.shah{at}kcl.ac.uk).

OBJECTIVES: This study sought to examine the role of Nox2 in the contractile dysfunction associated with pressure-overload left ventricular hypertrophy (LVH).

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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, together with greater increases in procollagen I and III mRNA expression.

CONCLUSIONS: The Nox2 oxidase contributes to the development of cardiac contractile dysfunction and interstitial fibrosis during pressure overload, although it is not essential for development of morphologic hypertrophy per se. These data suggest divergent downstream effects of Nox2 on different components of the overall response to pressure overload.

Abbreviations and Acronyms   ANF = atrial natriuretic factor   AngII = angiotensin II   EDPVR = end-diastolic pressure volume relation   ESPVR = end-systolic pressure volume relation   IVSD = interventricular septal thickness in diastole   LVEDD = left ventricular end-diastolic dimension   LVESD = left ventricular end-systolic dimension   LVH = left ventricular hypertrophy   NADPH = nicotinamide adenosine dinucleotide phosphate, reduced   ROS = reactive oxygen species   WT = wild-type

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