Abstract 139: Doca-salt Induced Vascular Dysfunction and Elevated Arginase Activity is Prevented in Haploinsufficient Rho Kinase 1 Mice

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Endothelial dysfunction is an established phenomenon in deoxycorticosterone acetate (DOCA)-salt hypertension. It has been reported that increased vascular arginase activity is involved with hypertension. We previously reported that the small GTPase, RhoA and Rho kinase (ROCK) are involved with activation of arginase in diabetic and angiotensin II hypertensive models. In this study, we hypothesized that partial knockdown of ROCK1 would prevent vascular endothelial dysfunction in DOCA-salt hypertension by blocking the rise in vascular arginase activity. We tested this concept using wild type and haploinsufficient ROCK1 knockout (R1 +/- ) mice, which were treated by DOCA pellet (50 mg) for 6 weeks and fed by 1% saline. Systolic blood pressure (SBP) was measured before and during 6 week treatment from wild type sham (WT), wild type DOCA (WT-D), ROCK1 sham (R1 +/- ) and ROCK1 DOCA (R1 +/- -D) mice (N = 6). SBP in WT-D mice rose over the 6 weeks treatment (from 104.6.6±2.6 mmHg to 124.4±5.6 mmHg) but not in WT mice (from 108.9±1.2 mmHg to 104.60±4.27 mmHg, p<0.05). At 6 weeks, SBP in R1 +/- -D mice (108.4±2.8 mmHg) was slightly higher than R1 +/- mice (98.9±1.6 mmHg, p<0.05). However, SBP in R1 +/- -D mice is significantly lower than WT-D mice during the whole treatment period. Additionally, vascular function was assessed in aortic segments (N = 4-6). We found WT-D mice exhibited a marked reduction of maximum endothelium-dependent relaxation (MER) to acetylcholine (57.6±4.3%, p<0.05) compared to WT mice (70.6±1.6%). Impairment of relaxation was absent in R1 +/- -D mice (MER: 82.9±2.8%, p<0.05). Arginase activity in aorta of WT-D mice (152.7±18.7 units) was ∼45% higher than in WT mice (105.3±2.2 units) and ∼225% higher than in R1 +/- -D mice (67.1±5.8 units). These data demonstrate involvement of ROCK1 in enhanced arginase activity and impaired endothelium dependent vasorelaxation in DOCA-salt hypertensive mice.