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 Nox4/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.

Rosuvastatin Prevents Angiotensin II-Induced Vascular Changes by Inhibition of Nad(P)H Oxidase and Cyclooxygenase-1.

FORNAI, MATTEO;ANTONIOLI, LUCA;IPPOLITO, CHIARA;SEGNANI, CRISTINA;BERNARDINI, NUNZIA;TADDEI, STEFANO;BLANDIZZI, CORRADO;VIRDIS, AGOSTINO
2013-01-01

Abstract

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 Nox4/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.
2013
Colucci, R; Fornai, Matteo; E., Duranti; Antonioli, Luca; I., Rugani; F., Aydinoglu; Ippolito, Chiara; Segnani, Cristina; Bernardini, Nunzia; Taddei, ...espandi
File in questo prodotto:
File Dimensione Formato  
2012-COLUCCI-BJP-ROSUVASTATIN.pdf

solo utenti autorizzati

Tipologia: Versione finale editoriale
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 2.15 MB
Formato Adobe PDF
2.15 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/203483
Citazioni
  • ???jsp.display-item.citation.pmc??? 5
  • Scopus 20
  • ???jsp.display-item.citation.isi??? 17
social impact