title: Rosuvastatin prevents angiotensin II-induced vascular changes by inhibition of NAD(P)H oxidase and COX-1.
abstract: OBJECTIVE
  NAD(P)H oxidase and COX-1 participate in vascular damage induced by angiotensin II. We investigated the effect of rosuvastatin on endothelial dysfunction, vascular remodelling, changes in extracellular matrix components and mechanical properties of small mesenteric arteries from angiotensin II-infused rats.
  
  
  METHODS
  Male rats received angiotensin II (120 ng·kg⁻¹ ·min⁻¹ , subcutaneously) for 14 days with or without rosuvastatin (10 mg·kg⁻¹ ·day⁻¹ , oral gavage) or vehicle. Vascular functions and morphological parameters were assessed by pressurized myography.
  
  
  RESULTS
  In angiotensin II-infused rats, ACh-induced relaxation was attenuated compared with controls, less sensitive to L-NAME, enhanced by SC-560 (COX-1 inhibitor) or SQ-29548 (prostanoid TP receptor antagonist), and normalized by the antioxidant ascorbic acid or NAD(P)H oxidase inhibitors. After rosuvastatin, relaxations to ACh were normalized, fully sensitive to L-NAME, and no longer affected by SC-560, SQ-29548 or NAD(P)H oxidase inhibitors. Angiotensin II enhanced intravascular superoxide generation, eutrophic remodelling, collagen and fibronectin depositions, and decreased elastin content, resulting in increased vessel stiffness. All these changes were prevented by rosuvastatin. Angiotensin II increased phosphorylation of NAD(P)H oxidase subunit p47phox and its binding to subunit p67phox, effects inhibited by rosuvastatin. Rosuvastatin down-regulated vascular Nox4/NAD(P)H isoform and COX-1 expression, attenuated the vascular release of 6-keto-PGF1α , and enhanced copper/zinc-superoxide dismutase expression.
  
  
  CONCLUSIONS
  Rosuvastatin prevents angiotensin II-induced alterations in resistance arteries in terms of function, structure, mechanics and composition. These effects depend on restoration of NO availability, prevention of NAD(P)H oxidase-derived oxidant excess, reversal of COX-1 induction and its prostanoid production, and stimulation of endogenous vascular antioxidant defences.
authors: Department of Internal Medicine, University of Pisa, Pisa, Italy.
authors: Rocchina
authors: R
authors: Colucci
authors: Matteo
authors: M
authors: Fornai
authors: Emiliano
authors: E
authors: Duranti
authors: Luca
authors: L
authors: Antonioli
authors: Ilaria
authors: I
authors: Rugani
authors: Fatma
authors: F
authors: Aydinoglu
authors: Chiara
authors: C
authors: Ippolito
authors: Cristina
authors: C
authors: Segnani
authors: Nunzia
authors: N
authors: Bernardini
authors: Stefano
authors: S
authors: Taddei
authors: Corrado
authors: C
authors: Blandizzi
authors: Agostino
authors: A
authors: Virdis
mesh_terms: D000804:Angiotensin II; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005464:Fluorobenzenes / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D055595:Mechanical Phenomena / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000627:therapeutic use*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D011743:Pyrimidines; D013449:Sulfonamides; D000804:Angiotensin II; D000068718:Rosuvastatin Calcium; D051545:Cyclooxygenase 1; C496513:Ptgs1 protein, rat; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat