Department of Internal Medicine, University of Pisa, Pisa, Italy.
Br J Pharmacol. 2013 Jun;169(3):554-66. doi: 10.1111/j.1476-5381.2012.02106.x.
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.
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.
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.
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.
烟酰胺腺嘌呤二核苷酸（NAD(P)H）氧化酶和环氧化酶-1（COX-1）参与血管紧张素Ⅱ诱导的血管损伤。本研究旨在探讨瑞舒伐他汀对血管紧张素Ⅱ输注大鼠血管内皮功能障碍、血管重构、细胞外基质成分变化及肠系膜小动脉力学特性的影响。
雄性大鼠接受血管紧张素Ⅱ（120ng·kg⁻¹·min⁻¹，皮下注射）输注 14 天，同时给予瑞舒伐他汀（10mg·kg⁻¹·天⁻¹，灌胃）或载体。通过加压血管张力描记法评估血管功能和形态参数。
与对照组相比，血管紧张素Ⅱ输注大鼠的乙酰胆碱诱导的舒张作用减弱，对 L-NAME 的敏感性降低，对 SC-560（COX-1 抑制剂）或 SQ-29548（前列腺素 TP 受体拮抗剂）的敏感性增强，抗氧化剂抗坏血酸或 NAD(P)H 氧化酶抑制剂可使舒张作用恢复正常。瑞舒伐他汀治疗后，乙酰胆碱诱导的舒张作用恢复正常，对 L-NAME 完全敏感，且不再受 SC-560、SQ-29548 或 NAD(P)H 氧化酶抑制剂的影响。血管紧张素Ⅱ增加了血管内超氧阴离子的产生、血管重构、胶原和纤维连接蛋白的沉积，并降低了弹力蛋白含量，导致血管僵硬增加。这些变化均被瑞舒伐他汀所预防。血管紧张素Ⅱ增加了 NAD(P)H 氧化酶亚基 p47phox 的磷酸化及其与亚基 p67phox 的结合，瑞舒伐他汀可抑制这些变化。瑞舒伐他汀下调了血管 Nox4/NAD(P)H 同工型和 COX-1 的表达，减轻了血管中 6-酮前列腺素 F1α 的释放，并增强了铜锌超氧化物歧化酶的表达。
瑞舒伐他汀可预防血管紧张素Ⅱ引起的阻力血管在功能、结构、力学和组成方面的改变。这些作用依赖于恢复一氧化氮的可用性，防止 NAD(P)H 氧化酶来源的氧化应激过度，逆转 COX-1 的诱导及其前列腺素的产生，以及刺激内源性血管抗氧化防御。
