Abstract 19767: Haploinsufficient Rho Kinase 1 (ROCK1) Mice Are Protected From Diabetes-induced Vascular Dysfunction Through Decreased Arginase Activation
Increased arginase activity and expression have been associated with various cardiovascular diseases. Arginase competes with nitric oxide synthase for their common substrate, L-arginine. Thus, nitric oxide production can be restricted in conditions of elevated arginase activity leading to vascular dysfunction. We have previously reported that the small GTPase, RhoA and Rho kinase (ROCK) are involved with activation of arginase in diabetes. Also, we showed that oxidative radicals increase arginase activity/expression via RhoA/ROCK pathways in endothelial cells. In this study, we hypothesized whether partial knockdown of ROCK-1 prevents vascular endothelial dysfunction by reducing arginase activity/expression in a streptozotocin diabetic model. We tested this concept using wild type (WT) and haploinsufficient ROCK1 (ROCK1+/−) mice. Vascular function was assessed in aortic segments from wild type (WT), wild type diabetic (WT-D), ROCK1+/− (R1) and ROCK1+/− diabetic (R1-D) mice (N = 4–6). Our studies show that WT-D mice exhibit a marked reduction of maximum endothelium-dependent relaxation (MER) to acetylcholine (ACh) (48.4±2.1%, p<0.05) compared to WT mice (62.1±1.5%). This impairment of relaxation was absent in R1-D mice (MER: 59.1±2.4%, p<0.05). Incubation of aortic rings with the arginase inhibitor (BEC, 100 μM, 1h) improved MER in both WT-D and R1-D mice. However, BEC treatment caused a significantly greater increase in MER of aorta from WT-D mice (21.5% increase) vs R1-D mice. This finding indicates a lower vascular arginase activity in R1-D vs WT-D mice. Additionally, incubation of aortic rings with either peroxynitrite decomposition catalyst, FeTPPS (10 μM, 1h) or NADPH oxidase inhibitor, apocynin (10 μM, 1h) further enhanced MER in R1-D mice (68.3±4.8% and 67.6±3.2%, respectively, p<0.05). In conclusion, these results indicate that partial knockdown of Rho kinase-1 (ROCK-1) prevents diabetes-induced impairment in endothelium dependent vasorelaxation by decreasing arginase activity. Moreover, scavenging oxidative radicals in addition to partial ROCK-1 deletion can further improve vascular function in diabetes.
- © 2010 by American Heart Association, Inc.