Abstract 17040: Selective Inhibition of Myocardial NADPH Oxidase with a Dominant-Negative Mutant of p67 phox Attenuates Angiotensin II-Induced Cardiac Hypertrophy in Adult Transgenic Mice

Abstract

Angiotensin (Ang) II infusion not only induces hypertrophy and fibrosis in mouse heart, but also causes hypertension and inflammation in vivo. Thus, the precise mechanisms of Ang II-induced cardiac hypertrophy are unclear. Recently, selective inhibition of Ang II receptor in vivo was reported to attenuate the increase of expression of myocardial NADPH oxidase (NOX) subunits including p67 phox in heart failure rats. To study the endogenous “cardiac” NOX role in vivo, we created a transgenic (Tg) mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NOX subunit p67 phox that prevented NOX activity. Age- and body weight (BW)-matched male Tg or WT C57BL/6 mice (12-14 weeks) were infused with either PBS or Ang II (0.7 mg/kg/day) for 2 weeks by an osmotic mini-pump. Echocardiography (echo) was then performed to determine the following parameters: left ventricular myocardial area (LVMA); LV wall thickness at end diastole; LV internal dimension at end diastole (IDd), LV end-diastolic volume (EDV), LV ejection fraction (EF), and LV mass. Mice were divided into 4 groups (6-8 mice/group) including WT-PBS, WT-Ang, Tg-PBS & Tg-Ang. The LVEDV, LVIDd & BW were similar between the PBS and Ang groups in both WT and Tg mice. The LVEF (mean 49-52%) was not statistically different among all groups. The WT-Ang mice showed significant increase in LVMA, LV mass & wall thickness indicating LV hypertrophy compared to WT-PBS. In contrast, Tg-Ang showed no significant difference in LVMA, LV mass & wall thickness vs. Tg-PBS, suggesting Ang-induced LV hypertrophy was inhibited in Tg mice (Table 1). Our echo data were confirmed by our results of heart weight (HW)/BW ratio and myocardium reactive oxygen species (ROS) measurement, showing the attenuation of the increase of both HW/BW ratio and ROS in TG-Ang mice vs. WT-Ang mice. In summary, our results showed that selective inhibition of myocardial NOX/p67 phox attenuates Ang II-Induced cardiac hypertrophy in Tg mice.