Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats.
OBJECTIVE
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 (11 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, gp91phox 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.
Mita
Shin-ichiro
S
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, 321-0293, Japan.
Kobayashi
Naohiko
N
Yoshida
Kohtaro
K
Nakano
Shigefumi
S
Matsuoka
Hiroaki
H
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D003331:Coronary Vessels / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005353:Fibronectins / Q000235:genetics; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020303:Rats, Inbred Dahl; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D000577:Amides; D024042:Collagen Type I; D024061:Collagen Type III; D004791:Enzyme Inhibitors; D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C495136:OLR1 protein, rat; D011725:Pyridines; D012333:RNA, Messenger; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; C508962:Tgfb1 protein, rat; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C108830:Y 27632; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; C497257:Prkce protein, rat; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020742:rhoA GTP-Binding Protein