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CLINICAL RESEARCH: VASCULAR DISEASE

Roles of Rho-Associated Kinase and Oxidative Stress in the Pathogenesis of Aortic Stiffness

Kensuke Noma, MD, PhD^_*, Chikara Goto, RPT, MS, PhD^_*, Kenji Nishioka, MD^_*, Daisuke Jitsuiki, MD^_*, Takashi Umemura, MD^_*, Keiko Ueda, MD, PhD, Masashi Kimura, MD, PhD, Keigo Nakagawa, MD, PhD, Tetsuya Oshima, MD, PhD, Kazuaki Chayama, MD, PhD, Masao Yoshizumi, MD, PhD^_*, James K. Liao, MD and Yukihito Higashi, MD, PhD, FAHA^_*,_*

^_* Cardiovascular Physiology and Medicine
Medicine and Molecular Science
Clinical Laboratory Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
Vascular Medicine Research Unit, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Manuscript received March 28, 2006; revised manuscript received June 16, 2006, accepted June 26, 2006.

^_* Reprint requests and correspondence: Dr. Yukihito Higashi, Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. (Email: yhigashi{at}hiroshima-u.ac.jp).

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.

Abbreviations and Acronyms   ACh = acetylcholine   cf-PWV = carotid-femoral pulse wave velocity   FBF = forearm blood flow   L-NMMA = N G-monomethyl-L-arginine   MDA-LDL = malondialdehyde-modified low-density lipoprotein   PWV = pulse wave velocity   ROCK = Rho-associated kinase   SNP = sodium nitroprusside   VSMC = vascular smooth muscle cells