Abstract 3428: The Nad(p)h Oxidase Component Nox4 Promotes Aging And Pathological Hypertrophy
A growing body of evidence shows that NAD(P)H oxidase is a major source of reactive oxygen species (ROS) in the cardiovascular system, including the heart, and is involved in the development of cardiac hypertrophy and failure. Among NAD(P)H oxidase proteins (Nox1–5), Nox4 is expressed in cardiac myocytes. Expression of Nox4 was increased by hypertrophic stimuli, such as transverse aortic constriction (TAC) (3.0 fold, p < 0.05). In order to determine how upregulation of Nox4 affects cardiac phenotype, we established mice with cardiac specific overexpression of wild-type Nox4 (Tg-Nox4) and catalytically inactive Nox4 (Tg-DN-Nox4 (P437H)) in which NADPH, the substrate of NAD(P)H oxidase, is unable to bind to Nox4. At 3 months of age, none of our transgenic lines of Tg-Nox4 and Tg-DN-Nox4 showed obvious phenotypic changes in the heart at baseline compared to non-transgenic mice (NTg). However, at the age of 13–14 months, Tg-Nox4 displayed slightly decreased left ventricular ejection fraction (EF) (65.3 ± 1.9 vs. 71.0 ± 0.8%, p < 0.05). Superoxide production in the heart, as evaluated by fluorescence of dihydroethidium, and the level of 8-hydroxylguanosine, an indicator of oxidative stress, was significantly enhanced in aged Tg-Nox4, and suppressed in aged Tg-DN-Nox4, compared with NTg. The effect of Nox4 upon cardiac phenotype was also studied under pressure overload at the age of 3 months. Fourteen days after TAC, Tg-Nox4 showed severe cardiac dysfunction (EF (%): 39.5 ± 12.5 vs. 67.5 ± 5.2, p < 0.05) with lung congestion (lung weight/body weight (BW) (mg/g): 13.5 ± 3.2 vs. 6.5 ± 0.4, p < 0.05) compared with NTg. TUNEL positive cells were significantly increased in Tg-Nox4 (~4-fold) and fibrosis was enhanced in Tg-Nox4. On the other hand, 30 days after TAC, Tg-DN-Nox4 showed less hypertrophy with preserved cardiac function and milder fibrosis, compared with NTg (LV weight/BW (mg/g): 3.8 ± 0.3 vs. 4.2 ± 0.4, EF (%): 73.5 ± 1.6 vs. 65.9 ± 1.7, p < 0.05). These findings suggest that during aging and pressure-overload, ROS produced from Nox4 promote cardiac dysfunction whereas suppression of endogenous Nox4 activity attenuates pathological cardiac hypertrophy.