Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats

被引:80
作者
Mita, S [1 ]
Kobayashi, N [1 ]
Yoshida, K [1 ]
Nakano, S [1 ]
Matsuoka, H [1 ]
机构
[1] Dokkyo Univ, Sch Med, Dept Hypertens & Cardiorenal Med, Mibu, Tochigi 3210293, Japan
关键词
Rho-kinase; nitric oxide synthase; oxidative stress; remodeling; oxidized low-density lipoprotein;
D O I
10.1097/00004872-200501000-00017
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
Objectives Rho-kinase plays a crucial role in various cellular functions. To elucidate molecular mechanisms of Rho-kinase-mediated cardiovascular remodeling in vivo, we evaluated whether a signaling pathway through Rho is involved, and whether Y-27632, a specific Rho-kinase inhibitor, stimulates endothelial nitric oxide synthase (eNOS) and suppresses the oxidative stress and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway in the left ventricle of Dahl salt-sensitive hypertensive (DS) rats. Methods Y-27632 (3 mg/kg per day) or vehicle were given for 5 weeks, from age 6 weeks to a stage of left ventricular hypertrophy (111 weeks). Age-matched Dahl salt-resistant (DR) rats fed the same diet served as a control group. Results Increased left ventricular weight in the hypertrophy stage was significantly ameliorated by Y-27632. Upregulated RhoA protein, Rho-kinase gene expression and myosin light-chain phosphorylation in the hypertrophy stage were suppressed by Y-27632. Increased expression of NAD(P)H oxidase p22phox, p47phox, gp91 phox and LOX-1 in DS rats were inhibited by Y-27632. Upregulated protein kinase Cepsilon and p65 nuclear factor-kappaB phosphorylation in DS rats was reduced by Y-27632. In contrast, downregulated eNOS expression in hypertrophy stage was upregulated by Y-27632, Y-27632 effectively inhibited vascular lesion formation, such as medial thickness and perivascular fibrosis, and suppressed transforming growth factor-beta1, type I and III collagen, and fibronectin gene expression. Conclusions Inhibiting the Rho-kinase pathway may play a key role in the cardioprotective effect on cardiovascular remodeling associated with eNOS and the oxidative stress-LOX-1 pathway in DS rats, and may be at least a potential therapeutic strategy for hypertension with cardiac hypertrophy. (C) 2005 Lippincott Williams Wilkins.
引用
收藏
页码:87 / 96
页数:10
相关论文
共 32 条
[21]   Identification of soluble forms of lectin-like oxidized LDL receptor-1 [J].
Murase, T ;
Kume, N ;
Kataoka, H ;
Minami, M ;
Sawamura, T ;
Masaki, T ;
Kita, T .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2000, 20 (03) :715-720
[22]   Enhanced expression of endothelial oxidized low-density lipoprotein receptor (LOX-1) in hypertensive rats [J].
Nagase, M ;
Hirose, S ;
Sawamura, T ;
Masaki, T ;
Fujita, T .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 237 (03) :496-498
[23]   AT1 receptor blockade reduces cardiac calcineurin activity in hypertensive rats [J].
Nagata, K ;
Somura, F ;
Obata, K ;
Odashima, M ;
Izawa, H ;
Ichihara, S ;
Nagasaka, T ;
Iwase, M ;
Yamada, Y ;
Nakashima, N ;
Yokota, M .
HYPERTENSION, 2002, 40 (02) :168-174
[24]   VASCULAR ENDOTHELIAL-CELLS SYNTHESIZE NITRIC-OXIDE FROM L-ARGININE [J].
PALMER, RMJ ;
ASHTON, DS ;
MONCADA, S .
NATURE, 1988, 333 (6174) :664-666
[25]   ABNORMAL ENDOTHELIUM-DEPENDENT VASCULAR RELAXATION IN PATIENTS WITH ESSENTIAL-HYPERTENSION [J].
PANZA, JA ;
QUYYUMI, AA ;
BRUSH, JE ;
EPSTEIN, SE .
NEW ENGLAND JOURNAL OF MEDICINE, 1990, 323 (01) :22-27
[26]   Rho proteins play a critical role in cell migration during the early phase of mucosal restitution [J].
Santos, MF ;
McCormack, SA ;
Guo, Z ;
Okolicany, J ;
Zheng, Y ;
Johnson, LR ;
Tigyi, G .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (01) :216-225
[27]   Rho and Rho kinase mediate thrombin-stimulated vascular smooth muscle cell DNA synthesis and migration [J].
Seasholtz, TM ;
Majumdar, M ;
Kaplan, DD ;
Brown, JH .
CIRCULATION RESEARCH, 1999, 84 (10) :1186-1193
[28]   Cellular and molecular mechanisms of coronary artery spasm - Lessons from animal models [J].
Shimokawa, H .
JAPANESE CIRCULATION JOURNAL-ENGLISH EDITION, 2000, 64 (01) :1-12
[29]   Reduced gene expression of vascular endothelial NO synthase and cyclooxygenase-1 in heart failure [J].
Smith, CJ ;
Sun, D ;
Hoegler, C ;
Roth, BS ;
Zhang, X ;
Zhao, G ;
Xu, XB ;
Kobari, Y ;
Pritchard, K ;
Sessa, WC ;
Hintze, TH .
CIRCULATION RESEARCH, 1996, 78 (01) :58-64
[30]   Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase [J].
Takemoto, M ;
Sun, JX ;
Hiroki, J ;
Shimokawa, H ;
Liao, JK .
CIRCULATION, 2002, 106 (01) :57-62