Abstract 19410: Myocardial-Specific Overexpression of a Dominant-Negative Mutant of NADPH Oxidase Subunit p67phox Attenuates Constitutively Active α&rtf-inf-start;1B&rtf-inf-end;-Adrenergic Receptor-Induced Cardiac Hypertrophy in Transgenic Mice
Transgenic (Tg) mice with cardiac-specific overexpression of a constitutively active mutant (CAM) α1B-adrenergic receptor (AR) was reported to induce cardiac hypertrophy. We had reported a Tg mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NADPH oxidase (NOX) subunit p67phox that inhibits NOX activity. To test the role of NOX in α1B-AR induced cardiac hypertrophy in vivo, these two Tg mice were crossed to generate Tg mice with cardiac-specific overexpression of both CAM-α1B-AR (A1B) and DN-p67phox (DNp67) transgenes. Age (12-week), gender, and body weight-matched mice from the following 4 groups (12 mice/group, each gender): wild type (WT), A1B, A1B/DNp67 & DNp67 were subjected to 2-D echocardiography (echo) to determine the following parameters: left ventricular myocardial area (LVMA), LV wall thickness at end diastole, LV ejection fraction (EF), and LV mass. The LVEF (mean 46-54%) was not statistically different among all groups. DNp67 mice showed no significant difference in LVMA, LV mass & wall thickness vs. WT (Table 1). The A1B mice showed significant increase (p<0.05) in LVMA, LV mass & wall thickness indicating LV hypertrophy vs. WT; whereas the A1B/DNp67 mice showed significantly (p<0.05) decreased hypertrophy vs. A1B mice but statistically no difference from the DNp67 mice. These data suggested that A1B-induced LV hypertrophy was attenuated in the A1B/DNp67 dual Tg mice. The hearts of the above mice were then harvested after echo, and their mRNA expression of fetal genes including ANF, skeletal alpha actin, β-MHC, and 4 fibrosis genes (no difference among 4 groups, n=3) was quantified using real-time RT-PCR. All the above 3 fetal genes were significantly increased in the A1B hearts vs. WT, and were all significantly (n=4, p<0.05) attenuated in the A1B/DNp67 mice. In summary, our results showed that selective inhibition of myocardial NOX subunit p67phox attenuated α1B-AR-induced cardiac hypertrophy in Tg mice. .
- Alpha-adrenergic receptor blockers
- Transgenic models
- Reactive oxygen intermediates
- © 2012 by American Heart Association, Inc.