Roles of rho-associated kinase and oxidative stress in the pathogenesis of aortic stiffness.
OBJECTIVE
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.
Noma
Kensuke
K
Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Goto
Chikara
C
Nishioka
Kenji
K
Jitsuiki
Daisuke
D
Umemura
Takashi
T
Ueda
Keiko
K
Kimura
Masashi
M
Nakagawa
Keigo
K
Oshima
Tetsuya
T
Chayama
Kazuaki
K
Yoshizumi
Masao
M
Liao
James K
JK
Higashi
Yukihito
Y
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D001018:Aortic Diseases / Q000209:etiology* / Q000503:physiopathology; D050197:Atherosclerosis / Q000209:etiology* / Q000503:physiopathology; D005542:Forearm / Q000098:blood supply; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D012039:Regional Blood Flow / Q000187:drug effects*; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D020030:Nitric Oxide Donors; D047428:Protein Kinase Inhibitors; D009599:Nitroprusside; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D000109:Acetylcholine; C049347:fasudil