title: Importance of NAD(P)H oxidase-mediated oxidative stress and contractile type smooth muscle myosin heavy chain SM2 at the early stage of atherosclerosis.
abstract: 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.
authors: Department of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
authors: Shinichi
authors: S
authors: Itoh
authors: Seiji
authors: S
authors: Umemoto
authors: Mitsuyuki
authors: M
authors: Hiromoto
authors: Yoichi
authors: Y
authors: Toma
authors: Yasuaki
authors: Y
authors: Tomochika
authors: Shumpei
authors: S
authors: Aoyagi
authors: Masakazu
authors: M
authors: Tanaka
authors: Takashi
authors: T
authors: Fujii
authors: Masunori
authors: M
authors: Matsuzaki
mesh_terms: 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
chemical_list: 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