主動脈結構失去完整性與彈力纖維結構嚴重受損是腹主動脈瘤的重要特徵。過氧化體增生受體γ(Peroxisome proliferator-activated receptor γ, PPARγ)已知可藉由抑制發炎與蛋白降解而減緩腹主動脈瘤進程。然而，在腹主動脈瘤發生過程中，PPARγ如何影響彈力纖維生成仍未完全了解。在人類腹主動脈瘤中，PPARγ大量表達在所有血管細胞中，包含免疫細胞與纖維母細胞。實驗結果發現PPARγ表達為25% 的PpargC/-小鼠主動脈中彈力纖維斷裂以及彈力纖維組成分子的表達量減少。在PPARγ表達為50% 的Pparg+/-小鼠則無以上現象。給予Pparg+/+小鼠血管張力素II (500 ng/kg/min)與高膽固醇飼料28天後，並無腹主動脈瘤發生，但Pparg+/-小鼠彈力纖維呈現平直，而PpargC/-小鼠主動脈中彈力纖維有更明顯的斷裂與破壞。而在給予高劑量血管張力素II (1000 ng/kg/min)後，73% PpargC/-小鼠在腎上主動脈處產生動脈瘤，其特徵包含，上腸繫膜動脈擴張，動脈外膜有膠原蛋白堆積與發炎細胞浸潤。雖然以doxycycline抑制基質金屬蛋白酶可減緩高劑量血管張力素II引起之PpargC/-小鼠動脈瘤擴張，但無法降低動脈瘤發生率，亦無法避免彈力纖維破壞。在纖維母細胞中利用抑制PPARγ可使elastin與fibulin-5表達下降，在血管平滑肌細胞則無此現象。染色質免疫沈澱分析顯示，在纖維母細胞中PPARγ可結合至fibulin-5基因體序列。這些結果指出PPARγ在腹主動脈瘤生成的重要性，PPARγ可調控正常彈力蛋白生成與保持彈力纖維完整性。另一方面，先前研究已發現，PPARγ基因功能缺失突變的病患有高血壓的症狀，而給予PPARγ活化劑的實驗動物和病人則顯示PPARγ活化劑具降低血壓的效果。結果顯示PPARγ低表達量小鼠收縮壓升高，但舒張壓並無明顯的差異，因此造成收縮壓與舒張壓之差─脈壓顯著上升。目前認為主動脈失去彈性，或主動脈硬度增加是造成脈壓升高的重要因子之一。因此，本實驗假設PPARγ缺失將會造成主動脈硬度增加，進而導致脈壓上升。首先利用臨床上用於判斷動脈硬化的參數，脈搏波傳遞速度(Pulse wave velocity, PWV) 檢驗PpargC/-小鼠是否有動脈硬化的情況。結果顯示PpargC/-小鼠的PWV顯著高於野生型小鼠，表示PpargC/-小鼠可能有動脈硬度增加現象。力學特性檢測則顯示PpargC/-小鼠主動脈延展性下降與硬度參數增加。給予中等劑量血管張力素II引發之彈力蛋白結構破壞會導致動脈中層硬度參數降低，而動脈外層堆積之膠原蛋白則造成PpargC/-腹主動脈延展性下降。由以上結果可知，PPARγ缺失可造成主動脈失去彈性，而使動脈硬度增加，最終導致脈壓上升。本研究也顯示PPARγ在血壓調控以及血管活性與主動脈結構完整性的重要性。綜括本篇研究結果，PPARγ是彈力纖維生成與腹主動脈瘤生成之重要調控因子，並顯示影響PPARγ表達量之基因變異可以作為檢驗病患腹主動脈瘤發生風險之指標。最終，在腹主動脈瘤疾病進程中，針對維持PPARγ表達量與活性之藥物治療更有助於保持彈力纖維完整性。

Loss of structural integrity and vascular dysfunction are key features of the development of vascular diseases. Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to attenuate progression of vascular disease through inhibition of inflammation and proteolytic degradation of elastic fiber. However, the role of PPARγ in elastic fiber component production remains unclear. In the first part of this study, we hypothesized that PPARγ plays key roles in maintenance of the elastic fiber integrity. In the aortas of transgenic mice expressing PPARγ at 25% normal levels (PpargC/- mice), we observed the fragmentation of elastic fibers and reduced expression of vital elastic fiber components of elastin and fibulin-5. These were not observed in mice with 50% normal PPARγ expression (Pparg+/- mice). Infusion of a moderate dose of angiotensin II (Ang II) (500 ng/kg/min) did not induce AAA but Pparg+/- aorta developed flattened elastic lamellae, whereas PpargC/- aorta showed severe destruction of elastic fibers. After infusion of Ang II at 1000 ng/kg/min, 73% of PpargC/- mice developed atypical suprarenal aortic aneurysms: superior mesenteric arteries were dilated with extensive collagen deposition in adventitia and infiltrations of inflammatory cells. Although matrix metalloproteinase inhibition by doxycycline somewhat attenuated the dilation of aneurysm, it did not reduce the incidence nor elastic lamella deterioration in Ang II-infused PpargC/- mice. Furthermore, PPARγ antagonism downregulated elastin and fibulin-5 in fibroblasts, but not in vascular smooth muscle cells. Chromatin immunoprecipitation assay demonstrated PPARγ binding in the genomic sequence of fibulin-5 in fibroblasts. Our results underscore the importance of PPARγ in AAA development though orchestrating proper elastogenesis and preserving elastic fiber integrity. Moreover, PPARγ has been reported to regulate vascular functions. Loss-of-function mutations in the PPARγ gene are implicated in human hypertension and PPARγ agonists decrease blood pressure both in animal models and in human patients. Our results showed that PpargC/- mice exhibited increased systolic blood pressure without significant change in diastolic blood pressure, resulting in a significant increase of pulse pressure. The loss of elasticity of the aorta, generally termed aortic stiffness, is thought to be one of the most important factors in the development of increased pulse pressure. Thus, we hypothesized that PPARγ deficiency caused aortic stiffening, resulting in the increase in pulse pressure. We found that aortic pulse wave velocity (PWV) was significantly increased in PpargC/- mice, suggesting the aortas of PpargC/- mice were stiffer than that of wild-type mice. The examination of mechanical properties showed that the distensibility was decreased and the Young’s modulus was increased in PpargC/- aortas. Infusion of a moderate dose of Ang II triggered a severe disruption of the medial elastic fiber, resulting in a low Young’s modulus in medial layer, whereas deposition of adventitial collagen fiber caused less distensible PpargC/- abdominal aortas. These results suggest that PPARγ deficiency causes loss of elasticity in aorta and development of aortic stiffening, further resulting in elevated pulse pressure. This study underscores the importance of PPARγ in the regulation of blood pressure, aortic stiffness and structural heterogeneity. Together, our study highlights PPARγ as a vital regulator in elastogenesis and AAA development, and suggests that genetic variants affecting PPARγ levels would be important for identifying patients at a higher risk for developing AAA. Furthermore, pharmacological intervention targeting PPARγ level/activity would be beneficial to preserve elastic fiber integrity during AAA initiation and development.

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