Pitavastatin restores vascular dysfunction in insulin-resistant state by inhibiting NAD(P)H oxidase activity and uncoupled endothelial nitric oxide synthase-dependent superoxide production.
3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) may benefit the vasculopathy of insulin resistance independent of its lipid-lowering effects. Because imbalance of nitric oxide (NO) and superoxide anion (O(2)(-)) formation may lead to vascular dysfunction, we investigated the effect of statin on vasomotion of insulin-resistant state to clarify the mechanism by which statin ameliorates the impaired function. In the isolated aorta, contraction induced by angiotensin II was more potent in Zucker fatty rats (ZF) compared with that in Zucker lean rats. Both angiotensin II type 1 receptor expression and O(2)(-) production were upregulated in ZF. In addition, deficiency of tetrahydrobiopterin (BH4) contributes to the endothelial dysfunction in ZF. Oral administration of pitavastatin for 8 weeks normalized angiotensin II-induced vasoconstriction and endothelial function in ZF. Pitavastatin treatment of ZF increased vascular BH4 content, which was associated with twofold increase in endothelial NO synthase (eNOS) activity as well as a 60% reduction in endothelial O(2)(-) production. The treatment also markedly downregulated protein expression of angiotensin II type 1 receptor and gp91phox, whereas expression of guanosine triphosphate cyclohydrolase I was upregulated. Pitavastatin restores vascular dysfunction by inhibiting NAD(P)H oxidase activity and uncoupled eNOS-dependent O(2)(-) production.
Shinozaki
Kazuya
K
Department of Pharmacology, Shiga University of Medical Science, Otsu, Shiga, Japan.
Nishio
Yoshihiko
Y
Ayajiki
Kazuhide
K
Yoshida
Yuichi
Y
Masada
Masahiro
M
Kashiwagi
Atsunori
A
Okamura
Tomio
T
D000804:Angiotensin II; D000818:Animals; D001011:Aorta; D015153:Blotting, Western; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006136:GTP Cyclohydrolase; D005786:Gene Expression Regulation; D007333:Insulin Resistance; D008297:Male; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009765:Obesity / Q000503:physiopathology; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011924:Rats, Zucker; D044140:Receptor, Angiotensin, Type 1; D012084:Renin-Angiotensin System / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D011804:Quinolines; D044140:Receptor, Angiotensin, Type 1; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D006136:GTP Cyclohydrolase; C108475:pitavastatin