Abstract 11244: Preventive Effect of Estrogen on Coupling Factor 6-Induced Salt-sensitive Hypertension and Cardiac Systolic Dysfunction in Mice
Background: We reported that in male coupling factor 6 (CF6) overexpressing transgenic mice (TG), high salt diet induced hypertension and cardiac systolic dysfunction with excessive radical generation. The role of gender in these CF6-mediated pathophysiologic conditions is unknown. We examined the effects of ovariectomy and estrogen replacement on hypertension, cardiac dysfunction, and Rac1 in female TG.
Methods and Results: Male and female TG and wild type mice (WT) at the age of 15 weeks were fed with normal salt or high salt diet during 60 weeks (n=5-7 in each group). Systolic (SBP) and diastolic blood pressures (DBP) and cardiac function were monitored. SBP and DBP (mmHg) were higher in TG fed with high salt diet than TG with normal salt diet during the period from 20 to 60 weeks in males (SBP, 124±2 vs 103±3; DBP, 81±2 vs 62±3, both p<0.05), but only at 60 weeks in females (SBP, 120±3 vs105±2; DBP, 81±3 vs 70±2, both p<0.05). BP elevation under high salt diet occur concomitantly with the decrease in left ventricular fractional shortening (male, 26.5±1.2% vs 34.2±1.3%; female, 28.9±0.7% vs 34.2±1.7%, both p<0.05). In WT, such changes were not observed. Female TG underwent bilateral ovariectomy with subcutaneous implantation of a 60-day-release pellet containing 0.18 mg estradiol (E2) or placebo, or sham operation (n=5-7 in each group). The mice were fed with high salt diet for 8 weeks, and BP and cardiac function were monitored. Rac1-GTP levels were determined using a pull-down assay. Bilateral ovariectomy with placebo induced hypertension (SBP, 120±10 vs 108±6, p<0.05) with systolic dysfunction (left ventricular fractional shortening, 32.8±5.8% vs 37.2±2.8%, p<0.05) at 8 weeks after initiation of high salt diet. The ratios of Rac1-GTP to total Rac1 were increased in ovariectomized TG by 3.8±0.5 times in the heart, and by 1.7±0.4 times in the kidney (both p<0.05). Estrogen replacement with E2 abolished CF6-mediated these pathophysiologic conditions under high salt diet.
Conclusions: Overexpression of CF6 induces salt-sensitive hypertension complicating systolic cardiac dysfunction, but the onset is delayed in females. Estrogen plays an important role in preventing these CF6-mediated pathophysiologic conditions presumably via downregulation of Rac1.
- © 2011 by American Heart Association, Inc.