Abstract 848: Mineralocorticoid Receptor Blockade Arrests Pressure Overload-Induced Left Ventricular Hypertrophy and Preserves Cardiac Function in Angiotensin II Type 1a Receptor Knockout Mice
Recently, we reported a angiotensin II independent production of aldosterone inducing left ventricular remodeling after myocardial infarction in angiotensin II type 1a receptor-knockout mice (KO). The goal of this study was to test the hypothesis that pressure overload-induced LVH in KO mice could be averted with mineralocorticoid receptor blockade. Pressure overload was induced by aortic banding in 3-week-old KO (n=12) and wild type (WT, n=30). Mice were treated with spironolactone (20 mg/kg/day) or vehicle for 4 weeks. At 4 weeks after surgery, LV weight to body weight was greater in the vehicle-treated banded groups (KO: 7.12±0.60 mg/g; WT: 7.60±0.30 mg/g) than in the spironolactone-treated banded groups (KO: 4.23±0.23 mg/g; WT: 5.38±0.24 mg/g) or sham-operated mice (KO: 4.18±0.26 mg/g, n=6; WT: 4.59±0.18 mg/g, n=8, p<0.05). LV fractional shortening was depressed in the vehicle-treated banded groups (KO: 17.8±0.9 %, WT: 17.6±0.6 %) than in the spironolactone-treated banded groups (KO: 30.9±2 %; WT: 27.2±0.8 %), with both groups being smaller than sham-operated mice (KO: 46.2±1.1 %; WT: 48.4±1.1 %, p<0.05). Pressure gradient across the transverse aorta was similar between the spironolactone-treated (KO: 93±1 mmHg, WT: 92±3 mmHg) and vehicle-treated mice (KO: 94±2 mmHg, WT: 92±1 mmHg). The LV mRNA level of cyp11b2 (aldosterone synthase gene) in the vehicle-treated banded groups increased 7 fold in KO and 6 fold in WT compared with each sham groups (p<0.05). In the vehicle-treated banded WT, LV mRNA levels were upregulated 7 fold in TGF-b, 8 fold in CTGF, 3 fold in type I collagen, 2 fold in type III collagen and 5 fold in BNP compared with the sham group (p<0.05). These upregulation was offset by spironolactone treatment (p<0.05). Interestingly, even in the vehicle treated banded KO, LV mRNA levels were upregulated 6 fold in TGF-b, 7 fold in CTGF, 7 fold in type I collagen, 2 fold in type III collagen and 5 fold in BNP compared with the sham group (p<0.05). These upregulation was offset by spironolactone treatment (p<0.05). Thus, pressure overload-induced hypertrophy and failure were observed even in the absence of angiotensin II signaling in mice. Angiotensin II independent production of aldosterone may play a role in mediating hypertrophy and failure in this model.