Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6727-32. doi: 10.1073/pnas.1115313109. Epub 2012 Apr 9.
Suppression of cyclooxygenase 2 (COX-2)-derived prostacyclin (PGI(2)) is sufficient to explain most elements of the cardiovascular hazard from nonsteroidal antinflammatory drugs (NSAIDs). However, randomized trials are consistent with the emergence of cardiovascular risk during chronic dosing with NSAIDs. Although deletion of the PGI(2) receptor fosters atherogenesis, the importance of COX-2 during development has constrained the use of conventional knockout (KO) mice to address this question. We developed mice in which COX-2 was deleted postnatally, bypassing cardiorenal defects exhibited by conventional KOs. When crossed into ApoE-deficient hyperlipidemic mice, COX-2 deletion accelerated atherogenesis in both genders, with lesions exhibiting leukocyte infiltration and phenotypic modulation of vascular smooth muscle cells, as reflected by loss of α-smooth muscle cell actin and up-regulation of vascular cell adhesion molecule-1. Stimulated peritoneal macrophages revealed suppression of COX-2-derived prostanoids and augmented 5-lipoxygenase product formation, consistent with COX-2 substrate rediversion. Although deletion of the 5-lipoxygenase activating protein (FLAP) did not influence atherogenesis, it attenuated the proatherogeneic impact of COX-2 deletion in hyperlipidemic mice. Chronic administration of NSAIDs may increasingly confer a cardiovascular hazard on patients at low initial risk. Promotion of atherogenesis by postnatal COX-2 deletion affords a mechanistic explanation for this observation. Coincident inhibition of FLAP may offer an approach to attenuating such a risk from NSAIDs.
抑制环氧化酶 2（COX-2）衍生的前列环素（PGI（2））足以解释非甾体抗炎药（NSAIDs）引起的心血管危害的大部分因素。然而，随机试验与 NSAIDs 慢性给药期间出现心血管风险一致。尽管 PGI（2）受体的缺失促进了动脉粥样硬化的形成，但 COX-2 在发育过程中的重要性限制了传统 KO 小鼠用于解决这一问题。我们开发了出生后 COX-2 缺失的小鼠，绕过了传统 KO 小鼠表现出的心肾缺陷。当将其与 ApoE 缺陷型高脂血症小鼠杂交时，COX-2 缺失加速了两性的动脉粥样硬化形成，病变表现为白细胞浸润和血管平滑肌细胞的表型调节，反映为α-平滑肌细胞肌动蛋白的丧失和血管细胞粘附分子-1 的上调。刺激腹膜巨噬细胞显示 COX-2 衍生的前列腺素的抑制和 5-脂氧合酶产物形成的增加，与 COX-2 底物的重新分配一致。尽管 5-脂氧合酶激活蛋白（FLAP）的缺失不影响动脉粥样硬化的形成，但它减轻了 COX-2 缺失在高脂血症小鼠中的促动脉粥样硬化作用。NSAIDs 的慢性给药可能会增加低初始风险患者的心血管危害。出生后 COX-2 缺失促进动脉粥样硬化的形成，为这一观察结果提供了一种机制解释。同时抑制 FLAP 可能为减轻 NSAIDs 的这种风险提供一种方法。
