Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Department of Anatomy, Gyeongsang National University School of Medicine, Jinju 660-751, Republic of Korea.
Int J Cardiol. 2014 Jun 1;174(1):43-50. doi: 10.1016/j.ijcard.2014.03.138. Epub 2014 Mar 21.
Abdominal aortic aneurysm (AAA) is an inflammatory disorder characterized by a localized degradation of connective tissue and apoptosis of vascular smooth muscle cells. This study examined whether the ligand-activated peroxisome proliferator-activated receptor (PPAR) δ can directly antagonize angiotensin II (Ang II)-induced AAA formation in apoE-deficient mice.
Six-month-old male apoE-deficient mice were infused with Ang II and/or GW501516 (1.44 and 3.3mg/kg/day, respectively) via osmotic mini-pumps. At day 28, aortic size was measured and tissues were collected for analyses. Co-infusion of GW501516, an activator of PPARδ, attenuated both the incidence and the severity of Ang II-induced AAA in apoE-deficient mice. Ligand-activated PPARδ also reduced infiltration of macrophages, resulting in significant decreases in chemotactic proteins such as monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and inducible nitric oxide synthase. The anti-inflammatory effect of GW501516 was associated with the suppression of apoptotic cell death, along with the inhibition of medial smooth muscle cell loss and focal elastin destruction, which leads to a medial dissection and aortic rupture. These ameliorative effects of GW501516 on Ang II-induced aneurysm were correlated with increased expression of extracellular matrix (ECM) proteins, such as types I and III collagen, fibronectin, and elastin, along with the up-regulation of transforming growth factor-β1. In addition, ligand-activated PPARδ also increased the expression of tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3, while it strongly suppressed that of matrix metalloproteinase-2.
PPARδ attenuates Ang II-induced AAA formation by regulating ECM homeostasis and inflammatory responses, suggesting a novel strategy for the treatment of AAA.
腹主动脉瘤（AAA）是一种炎症性疾病，其特征为局部结缔组织降解和血管平滑肌细胞凋亡。本研究旨在探讨配体激活的过氧化物酶体增殖物激活受体（PPAR）δ能否直接拮抗载脂蛋白 E 缺陷（apoE-/-）小鼠的血管紧张素 II（Ang II）诱导的 AAA 形成。
6 月龄雄性 apoE-/-小鼠通过渗透微型泵输注 Ang II 和/或 GW501516（分别为 1.44 和 3.3mg/kg/天）。在第 28 天，测量主动脉大小并收集组织进行分析。共输注 GW501516（PPARδ 激动剂）可减轻 apoE-/-小鼠 Ang II 诱导的 AAA 的发生率和严重程度。配体激活的 PPARδ 还减少了巨噬细胞浸润，导致趋化蛋白如单核细胞趋化蛋白-1、巨噬细胞炎症蛋白-1β和诱导型一氧化氮合酶显著减少。GW501516 的抗炎作用与抑制凋亡细胞死亡有关，同时抑制中膜平滑肌细胞丢失和局灶性弹力蛋白破坏，导致中膜夹层和主动脉破裂。GW501516 对 Ang II 诱导的动脉瘤的这些改善作用与细胞外基质（ECM）蛋白如 I 型和 III 型胶原、纤维连接蛋白和弹力蛋白的表达增加有关，同时还上调转化生长因子-β1。此外，配体激活的 PPARδ 还增加了组织金属蛋白酶抑制剂（TIMP）-2 和 TIMP-3 的表达，同时强烈抑制基质金属蛋白酶-2 的表达。
PPARδ 通过调节 ECM 动态平衡和炎症反应来减轻 Ang II 诱导的 AAA 形成，提示了治疗 AAA 的新策略。
