Department of Internal Medicine, University of Pisa, Pisa, Italy.
Eur Heart J. 2012 Sep;33(17):2225-34. doi: 10.1093/eurheartj/ehr138. Epub 2011 May 23.
The aim of this study was to investigate the role of cyclooxygenase (COX)-1 on vascular alterations in structure, mechanics, and extracellular matrix (ECM) components induced by angiotensin (Ang) II in mesenteric arteries from wild-type (WT) and COX-1 knockout (COX-1(-/-)) mice.
Animals were infused with vehicle or Ang II (400 ng/kg/min, s.c.) ± SC-560 (COX-1 inhibitor), DFU (COX-2 inhibitor), or SQ-29548 (TP receptor antagonist). After 2 weeks, vessels were isolated and exposed to intraluminal pressures (3-140 mmHg, pressurized myograph) to determine mechanical properties. Angiotensin II-induced vascular hypertrophic remodelling in WT was reversed by SC-560 or SQ-29548, but unaffected by DFU. Angiotensin II increased vessel stiffness (P< 0.01), this effect being ameliorated by SC-560 or SQ-29548, but unmodified by DFU. Angiotensin II failed to modify vessel elasticity in COX-1(-/-) mice. In WT vessels, Ang II enhanced COX-1 immunostaining, induced collagen and fibronectin depositions and decreased elastin content (P< 0.01). These effects were reversed by SC-560 or SQ-29548, but unaffected by DFU. In COX-1(-/-) mice, Ang II did not affect ECM contents. In WT, Ang II increased COX-1 and decreased COX-2 expression, and enhanced the vascular release of 6-keto-PGF1α which was prevented by COX-1 blockade. Human coronary artery smooth muscle cells, incubated with Ang II, showed an increased expression of procollagen I, which was abrogated by SC-560 or SQ-29548.
Angiotensin II-induced alterations of resistance arteries in structure, mechanics, and ECM composition were prevented by COX-1 inhibition and TP receptor antagonism, indicating that Ang II-mediated vascular damage is mediated by COX-1-derived prostanoid prostacyclin, activating TP receptors.
本研究旨在探讨环氧合酶（COX）-1 在血管紧张素（Ang）II 诱导的肠系膜动脉结构、力学和细胞外基质（ECM）成分改变中的作用。
动物给予载体或 Ang II（400ng/kg/min，皮下注射）± SC-560（COX-1 抑制剂）、DFU（COX-2 抑制剂）或 SQ-29548（TP 受体拮抗剂）。2 周后，分离血管并暴露于腔内压力（3-140mmHg，加压肌动描记器）以确定力学特性。WT 中 Ang II 诱导的血管肥大重塑被 SC-560 或 SQ-29548 逆转，但不受 DFU 影响。Ang II 增加血管僵硬度（P<0.01），SC-560 或 SQ-29548 可改善该作用，但 DFU 无影响。Ang II 未能改变 COX-1（-/-）小鼠的血管弹性。在 WT 血管中，Ang II 增强 COX-1 免疫染色，诱导胶原和纤维连接蛋白沉积，并降低弹性蛋白含量（P<0.01）。这些作用被 SC-560 或 SQ-29548 逆转，但不受 DFU 影响。在 COX-1（-/-）小鼠中，Ang II 不影响 ECM 含量。在 WT 中，Ang II 增加 COX-1 表达，降低 COX-2 表达，并增强血管释放 6-酮-PGF1α，COX-1 阻断可预防该作用。用 Ang II 孵育的人冠状动脉平滑肌细胞，前胶原 I 的表达增加，该作用被 SC-560 或 SQ-29548 阻断。
COX-1 抑制和 TP 受体拮抗可预防 Ang II 诱导的阻力血管结构、力学和 ECM 组成的改变，表明 Ang II 介导的血管损伤是由 COX-1 衍生的前列环素前列腺素 I 介导的，激活 TP 受体。
