Abstract 17329: Myocardial-Specific Overexpression of a Dominant-Negative Mutant of NADPH Oxidase Subunit p67 phox Attenuates Pressure-Overload-Induced Cardiac Hypertrophy in Adult Transgenic Mice

Abstract

We had reported a transgenic (Tg) mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NADPH oxidase (NOX) subunit p67 phox that inhibits NOX activity. In order to test the role of NOX in pressure-overload-induced cardiac hypertrophy in young adult mice, age and body weight (BW)-matched male homozygous Tg and wild type (WT) C57BL/6 mice (10-12 weeks) were subjected to transverse aortic constriction (TAC) or sham operation. Four-week post TAC, 2-D echocardiography (echo) was performed to determine the following cardiac 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), LV mass & aortic pressure gradient. Mice were divided into 4 groups (15-24 mice/group) including WT-sham, WT-TAC, Tg-sham & Tg-TAC. The LVEDV, LVIDd & BW were similar among all groups. The LVEF (mean 48-53%) was not statistically different among all groups. The aortic pressure gradient was between 30-60 mmHg in TAC mice and was statistically similar between the Tg and WT groups (45.3 ±1.7 vs. 50.4 ± 2.1 mmHg, p =0.1). Tg-sham showed no significant difference in LVMA, LV mass & wall thickness vs. WT-sham (Table 1). The WT-TAC mice showed significant increase in LVMA, LV mass & wall thickness indicating LV hypertrophy. The Tg-TAC mice also showed mild increase in the above parameters with the LV wall thickness statistically different from Tg-sham. However, these increases in Tg-TAC mice were significantly ( p <0.05) smaller than those in WT-TAC mice, suggesting TAC-induced LV hypertrophy was attenuated in Tg mice. Our echo finding was also confirmed by our results of heart weight/BW ratio, ANF mRNA expression, and histological study of the LV myocardium. In summary, our results showed that selective inhibition of myocardial NOX subunit p67 phox attenuated chronic pressure-overload-Induced cardiac hypertrophy in young adult mice.