Roles of rho-associated kinase and oxidative stress in the pathogenesis of aortic stiffness

Abstract

Objectives: The purpose of this study was to determine the relationship between Rho-associated kinase (ROCK) activity and aortic stiffness in humans.

Background: Epidemiologic studies have shown that there is a relationship between aortic stiffness and cardiovascular complications. Recent evidence suggests that ROCK plays an important role in the process of atherosclerosis.

Methods: We evaluated the forearm blood flow (FBF) response to sodium nitroprusside (SNP), a nitric oxide donor, acetylcholine (ACh), an endothelium-dependent vasodilator, and fasudil, a specific ROCK inhibitor, in 51 healthy male subjects (mean age 45.6 +/- 3.0 years). The FBF was measured by using a strain-gauge plethysmography. Carotid-femoral pulse wave velocity (cf-PWV) was measured to assess the aortic stiffness using a pulse wave velocimeter.

Results: Intra-arterial infusion of SNP alone, ACh alone, or fasudil alone and after co-infusion of N(G)-monomethyl-L-arginine (L-NMMA), a nitric-oxide synthase inhibitor, significantly increased FBF in a dose-dependent manner (p < 0.01). Multivariate analysis showed that age and number of pack-years smoked were independent predictors of ROCK activity before or after co-infusion of L-NMMA (p < 0.01) and that age and ROCK activity before or after co-infusion of L-NMMA were independent predictors of cf-PWV (p < 0.01). The concentration of serum malondialdehyde-modified low-density lipoprotein, an index of oxidative stress, was significantly correlated with ROCK activity before and after co-infusion of L-NMMA and cf-PWV (p < 0.01).

Conclusions: These findings suggest that aging and accumulating smoking habit, which might induce excessive oxidative stress, are involved in ROCK activity in the vasculature, leading to an increase in aortic stiffness in humans.

Figure 1. FBF Response to SNP

Results are presented as mean ± SEM. The probability value refers to a comparison of time course curves by analysis of variance for repeated measurements. *p < 0.01 vs. basal forearm blood flow (FBF) assessed by Bonferroni correction. SNP = sodium nitroprusside.

Figure 2. FBF Response to ACh

Results are presented as mean ± SEM. The probability value refers to a comparison of time course curves by analysis of variance for repeated measurements. *p < 0.05; †p < 0.01 vs. basal forearm blood flow (FBF) assessed by Bonferroni correction. ACh = acetylcholine.

Figure 3. FBF Response to Fasudil Alone and After Co-Infusion of L-NMMA

Results are presented as mean ± SEM. The probability value refers to a comparison of time course curves by analysis of variance for repeated measurements in each group. *p < 0.01 vs. basal forearm blood flow (FBF) of fasudil alone; †p < 0.01 vs. basal FBF after co-infusion of N^G-Monomethyl-L-arginine (L-NMMA) assessed by Bonferroni correction.