Abstract 12909: Rho Kinase as an Important Mediator of Aortic Stiffness
Background: Rho kinases (ROCK1 and ROCK2) are important regulators of the actin cytockeleton and cellular contraction. Because advancing age is associated with increased vascular stiffening, we investigated whether aortic ROCK activity is increased with age and whether aortic stiffness could be attenuated by ROCK deletion.
Methods and Results: Compared to 4-month-old mice, 11- and 20-month-old mice exhibited increased aortic ROCK activity but not systemic blood pressure (BP). This correlated with increased aortic stiffness as determined by pulse wave velocity (PWV at 4, 11, and 20 months: 4.43 ± 0.42, 6.66 ± 0.53, and 7.22 ± 0.56 m/sec; P<0.05 compared to 4 month). Compared to WT male mice at 4 months of age, aortic stiffness was slightly less in ROCK1+/- and ROCK2+/- mice (PWV: 3.55 ± 0.25 and 3.33 ± 0.20 m/sec, P<0.05). With increasing age (11 and 20 months), there was substantially less increase in aortic stiffening in ROCK1+/- and ROCK2+/- mice compared to WT mice, with the greatest attenuation observed in ROCK2+/- mice. Indeed, PWV in 4-month-old male WT mice was comparable to that of 11-month-old male ROCK1+/- mice and 20-month-old male ROCK2+/- mice. Aortic stiffness was also induced in WT, ROCK1+/- and ROCK2+/- mice with angiotensin (Ang) II (500 ng/kg/min by osmotic mini-pump) and the endothelial nitric oxide synthase inhibitor, L-NAME (0.5 g/L, po in drinking water), for 4 weeks. Compared to saline, treatment with Ang II/L-NAME increased systolic BP, pulse and augmented pressures, peripheral resistance (Z0), characteristic impedance (Zc), intrinsic stiffness (E), wall thickness, and PWV in WT mice, but to a lesser extent, in ROCK1+/- and ROCK2+/- mice. This correlated with greater differences between systolic and diastolic internal aortic root diameters suggesting greater vascular compliance or less stiffness. Indeed, decreased aortic stiffness in ROCK1+/- and ROCK2+/- mice was associated with preservation of elastic fibers and less deposition of mature collagen fibers.
Conclusion: These findings indicate that ROCK2, and to a lesser extent, ROCK1, play an important role in the thickening and stiffening of the aorta. These results suggest that inhibition of ROCKs could attenuate age- and risk factor-associated increase in aortic stiffness.
- © 2011 by American Heart Association, Inc.