Premium
Rosuvastatin prevents angiotensin II ‐induced vascular changes by inhibition of NAD ( P ) H oxidase and COX ‐1
Author(s) -
Colucci Rocchina,
Fornai Matteo,
Duranti Emiliano,
Antonioli Luca,
Rugani Ilaria,
Aydinoglu Fatma,
Ippolito Chiara,
Segnani Cristina,
Bernardini Nunzia,
Taddei Stefano,
Blandizzi Corrado,
Virdis Agostino
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02106.x
Subject(s) - rosuvastatin , angiotensin ii , chemistry , endocrinology , nad(p)h oxidase , apocynin , nad+ kinase , medicine , oxidase test , vasoprotective , pharmacology , nadph oxidase , biochemistry , oxidative stress , receptor , nitric oxide , enzyme
Background and Purpose 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. Experimental Approach 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. Key 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 N ox4/ NAD ( P ) H isoform and COX ‐1 expression, attenuated the vascular release of 6‐keto‐ PGF 1α , and enhanced copper/zinc‐superoxide dismutase expression. Conclusion and Implications 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.