NADPH oxidase isoforms and anti-hypertensive effects of atorvastatin demonstrated in two animal models.
Beneficial effects of statins on cardiovascular diseases have been attributed to decreased generation of reactive oxygen species (ROS). We tested the hypothesis that atorvastatin protects against the development of hypertension by reducing levels of NADPH oxidase-derived ROS in two hypertensive animal models. Atorvastatin was given to mice chronically infused with angiotensin (Ang) II or to apolipoprotein E (ApoE)-deficient mice fed a high-fat diet. Increased mean blood pressure (MBP) demonstrated in both animal models was significantly suppressed by atorvastatin with reduced ROS production in the aorta. Treatment with atorvastatin did not alter the mRNA level of NOX1, a catalytic subunit of NADPH oxidase, but decreased the levels of other NOX isoforms, NOX2 and NOX4, in the ApoE-deficient mice fed a high-fat diet. In the Ang II-infused model treated with statin, only the NOX4 mRNA level was reduced. Membrane translocation of Rac1 was significantly reduced in the Ang II-infused mice treated with atorvastatin. Finally, atorvastatin administered to Ang II-infused mice lacking the Nox1 gene elicited an additional decline in MBP compared to Nox1-deficient mice treated with vehicle. Together, these findings suggest that reduced expression and activity of the isoforms of NADPH oxidase, involving NOX1, NOX2, and possibly NOX4, mediate the anti-hypertensive effect of atorvastatin.
Cui
Wenhao
W
Department of Pharmacology, Kyoto Prefectural University of Medicine, Japan.
Matsuno
Kuniharu
K
Iwata
Kazumi
K
Ibi
Masakazu
M
Katsuyama
Masato
M
Kakehi
Tomoko
T
Sasaki
Mika
M
Ikami
Kanako
K
Zhu
Kai
K
Yabe-Nishimura
Chihiro
C
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D000069059:Atorvastatin; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004041:Dietary Fats / Q000009:adverse effects; D004996:Ethidium; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000235:genetics
D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D004041:Dietary Fats; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007527:Isoenzymes; D011758:Pyrroles; D000804:Angiotensin II; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D004996:Ethidium