Importance of NAD(P)H oxidase-mediated oxidative stress and contractile type smooth muscle myosin heavy chain SM2 at the early stage of atherosclerosis.
BACKGROUND
Increased vascular oxidative stress induced by hyperlipidemia may alter the phenotype of vascular smooth muscle (SM) cells and play a crucial role in the progression of atherosclerosis. To clarify the mechanisms underlying vascular dysfunction and oxidative stress in hypercholesterolemia, we compared the effects of antioxidant probucol with those of pravastatin on aortic stiffness, phenotypic modulation, oxidative stress, and NAD(P)H oxidase essential subunit p22(phox) expression in aortic medial SM cells of cholesterol-fed rabbits by using color image analysis of immunostained sections.


RESULTS
Japanese white male rabbits were fed either normal chow or 1% cholesterol diet for 14 weeks. After the first 7 weeks, cholesterol-fed rabbits were further divided into 3 groups: those fed with cholesterol feed only and those additionally given pravastatin (10 mg/d) or probucol (1.3 g/d) for the last 7 weeks. Within 7 weeks of treatment, probucol improved aortic stiffness more effectively than did pravastatin, inhibiting phenotypic modulation by selectively upregulating contractile-type SM myosin heavy chain isoform SM2 and by reducing both p22(phox) and superoxide content in medial SM cells of cholesterol-fed rabbit aorta. No significant differences in cholesterol levels, superoxide content, and endothelial NO synthase levels in the intima, aortic morphology and fibrosis, and synthetic-type myosin heavy chain in medial SM cells were observed between the 2 drug-treated groups.


CONCLUSIONS
These results suggest that oxidative stress and SM2 in medial SM cells might be important factors for vascular dysfunction, and strategies aimed at blocking NAD(P)H oxidase and upregulating SM2 may have therapeutic potential against the progression of atherosclerosis in hypercholesterolemia.
Itoh
Shinichi
S
Department of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Umemoto
Seiji
S
Hiromoto
Mitsuyuki
M
Toma
Yoichi
Y
Tomochika
Yasuaki
Y
Aoyagi
Shumpei
S
Tanaka
Masakazu
M
Fujii
Takashi
T
Matsuzaki
Masunori
M
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001161:Arteriosclerosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004548:Elasticity / Q000187:drug effects; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy; D008297:Male; D026901:Membrane Transport Proteins; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D009252:NADPH Dehydrogenase / Q000378:metabolism; D019255:NADPH Oxidases; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D011341:Probucol / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D011817:Rabbits; D024745:Smooth Muscle Myosins / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D000199:Actins; D000924:Anticholesteremic Agents; D000975:Antioxidants; D026901:Membrane Transport Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D013481:Superoxides; D002784:Cholesterol; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; C086986:CYBA protein, human; D009252:NADPH Dehydrogenase; D024745:Smooth Muscle Myosins; D018995:Myosin Heavy Chains; D017035:Pravastatin; D011341:Probucol