Critical role of bradykinin-eNOS and oxidative stress-LOX-1 pathway in cardiovascular remodeling under chronic angiotensin-converting enzyme inhibition.
To elucidate the molecular mechanisms of the cardioprotective effect of angiotensin-converting enzyme (ACE) inhibitors, we evaluated whether the effect of quinapril involved in bradykinin-endothelial nitric oxide synthase (eNOS) and oxidative stress-lectin-like oxidized LDL receptor-1 (LOX-1) pathway. Dahl salt-sensitive hypertensive (DS) rats were fed a diet containing 8% NaCl and treated with one of the following drug combinations for 5 weeks, from 6 weeks of age to left ventricular hypertrophy stage (11 weeks): vehicle; quinapril; quinapril plus the bradykinin B2 receptor antagonist FR172357; the NAD(P)H oxidase inhibitor apocynin; or quinapril plus apocynin. eNOS expression, which was decreased in hypertrophy stage, was significantly increased by quinapril and/or apocynin, but not by quinapril plus FR172357. Upregulated expression of NAD(P)H oxidase p22phox, p47phox, gp91phox and LOX-1 was significantly decreased by quinapril to a similar degree as after treatment with apocynin, but not by quinapril plus FR172357. Quinapril and/or apocynin treatment effectively ameliorated left ventricular weight and vascular changes such as increase in medial thickness and perivascular fibrosis and suppressed expression of transforming growth factor-beta1, type I collagen and fibronectin mRNA, but not that of quinapril plus FR172357. These results suggest that the ACE inhibitor quinapril may have cardioprotective effects in this model of hypertension mediated at least in part through effects on the bradykinin-eNOS and oxidative stress-LOX-1 pathway.
Kobayashi
Naohiko
N
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. nao-koba@dokkyomed.ac.jp
Honda
Takeaki
T
Yoshida
Kohtaro
K
Nakano
Shigefumi
S
Ohno
Tomoyuki
T
Tsubokou
Yusuke
Y
Matsuoka
Hiroaki
H
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000096:biosynthesis*; D002319:Cardiovascular System / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D018384:Oxidative Stress; D000077583:Quinapril; D051381:Rats; D051127:Scavenger Receptors, Class E / Q000378:metabolism*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D000098:Acetophenones; D005353:Fibronectins; D051127:Scavenger Receptors, Class E; D044005:Tetrahydroisoquinolines; D014665:Vasodilator Agents; D003094:Collagen; C056165:acetovanillone; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; D000077583:Quinapril; D001920:Bradykinin