腹主動脈瘤是一個嚴重威脅生命的心血管疾病，在65歲以上的人口，其發生率約4-8%。腹主動脈瘤通常並無明顯的症狀，但一旦破裂，它的致死率超出80%，為臨床上嚴重的問題。截至目前，外科手術是治療腹主動脈瘤唯一有效的方法，因此急需新的治療方法。在手術中取得的腹主動脈瘤組織有三個主要特徵：組織呈現慢性發炎的狀態，細胞外間質的破壞性重塑及血管平滑肌細胞的減少。但是腹主動脈瘤的形成及其之後的演變過程機制仍然不詳。為了進一步解開這個謎題，我們的實驗室在蘭嶼迷你豬以人工血管在腎動脈下方的腹主動脈進行窄化進而誘發腹主動脈瘤生成，建立了一個新的動物模式。在此模式中，窄化手術12週後，在血管遠端會形成腹主動脈瘤。間質金屬蛋白酶(MMP)會分解維持血管壁彈性及強度的細胞外間質蛋白，包括彈性蛋白和膠原蛋白。在正常的生理情況下，間質金屬蛋白酶的活性會受內生性的間質金屬蛋白酶之抑制蛋白(TIMPs)調控。因此，本研究的目的是探討在窄化誘發腹主動脈瘤生成的過程中，間質金屬蛋白酶和其抑制蛋白在不同的時間點與腹主動脈不同部位的特異性表現。我偵測間質金屬蛋白酶和其抑制蛋白在窄化4週，8週和12週後，在血管窄化的遠端和近端的表現量，並與腎動脈上方的腹主動脈進行對照。對照組則是接受同樣的手術程序但未進行窄化。各種間質金屬蛋白酶的基因表現以即時聚合酶連鎖反應去定量。在窄化後4週，MMP3, MMP7, MMP9 和MMP13mRNA在遠端血管的表現量較近端、腎動脈上端或兩者，有顯著性上升。此外，實驗組的MMP19 mRNA在遠端血管的表現量相較於另兩段和對照組都有明顯的增加。相反地，MMP15 mRNA則在腎動脈上端較窄化近端與對照組有明顯的上升。在偵測MMP基因表現量後，我以西方墨點法偵測MMP2,MMP9和MMP13的蛋白質表現量。結果顯示，MMP2與MMP13在各段腹主動脈中維持穩定的表現量，並未因窄化而有顯著的變化。MMP9的蛋白表現量與其活性在窄化遠端呈現上升的趨勢，由於豬個體間的差異性甚大,在統計上並不顯著。相對地，MMP9的蛋白與活性在腎動脈上端的腹主動脈皆無法偵測到。另外，在四個TIMPs當中, 腎動脈上端的腹主動脈的TIMP2和TIMP3 mRNA表現量在窄化4週後較另兩段的腹主動脈顯著地高，其中，TIMP3 mRNA的表現量在窄化8週後仍維持在較高的值。但TIMP3的蛋白質表現量並未因血管窄化而有明顯的變化。以螢光雙染去檢視表現MMP9的細胞，實驗結果顯示浸潤到血管壁外膜層的巨噬細胞多數會表現MMP9，以窄化8週後最明顯。相反地，在血管壁中的平滑肌細胞並未偵測到MMP9的表現。TIMP3的螢光染色結果顯示，TIMP3分佈在血管中層的外圍與外膜層，尤以血管壁外膜層的小血管最為明顯。此外，在窄化遠端的血管壁外膜層的小血管，可觀察到MMP9和TIMP3的共同表現。由於共同表現的區域不多，推測MMP9與TIMP3有限的相互作用並不足以保護血管不至於膨大。綜合上述的結果，在窄化所誘發的腹主動脈瘤生成的過程中，各種MMPs與TIMPs隨著時間與血管壁的部位而有不同的變化，這些變化可能促使腹主動脈瘤的形成與（或）演變。

Abdominal Aortic Aneurysm (AAA) is a life-threatening cardiovascular disease that affects 4% to 8% of the population over 65 years old. AAA usually remains asymptomatic but causes a mortality rate over 80% when rupture occurs. Up to now, surgery is the sole effective treatment for AAA and new therapeutics are urgently needed. AAA tissues obtained at surgery are characterized by chronic inflammation, destructive remodeling of the extracellular matrix (ECM) and depletion of vascular smooth muscle cells (VSMCs). However, mechanisms underlying the initial AAA formation and further progression remain poorly understood. To address this problem, our laboratory established a coarctation-induced AAA model in Taiwanese Lanyu mini pigs, in which coarctation of an infrarenal abdominal aorta (AA) segment for 12 weeks induces AAA formation in the distal segment. Matrix metalloproteinases (MMPs) degrade ECM proteins, particularly elastin and collagen which maintain the elasticity and strength of the aorta. MMP activities are in turn regulated by endogenous tissue inhibitors of matrix metalloproteinases (TIMPs). Therefore, this study is aimed to examine the temporal and spatial expression of MMPs and TIMPs during coarctation-induced AAA formation. The expression of MMPs and TIMPs was examined at 4 weeks (4w), 8 weeks (8w), and 12 weeks (12w) post-coarctation in the AA segments proximal and distal to coarctation using suprarenal AA segment as a reference. Sham group which received similar surgical procedure without coarctation was used as the control. Via real-time polymerase chain reaction (PCR) analysis, the mRNA levels of MMP3, MMP7, MMP9, MMP13, and MMP19 were elevated in the distal AA segment at 4w compared to either one or both of the other two segments. In addition, MMP19 mRNA was elevated in the experimental group at 4w compared with sham group. In contrast, MMP15 mRNA exhibited an increase in the suprarenal AA segment compared with the proximal AA segment and sham group at 4w post-coarctation. Protein expression of MMP2, MMP9 and MMP13 was further investigated with immunoblotting. No apparent change was detected for MMP2 and MMP13 which are constitutively expressed in the aorta. An apparent increase was detected for MMP9 expression and gelatinolytic activity in the distal AA segment over the investigation period though the increase did not reach significant level as a result of large variation among experimental animals. In contrast, neither MMP9 protein expression nor gelatinolytic activity was detected in the suprarenal AA segment. Among four TIMPs, mRNA expression of TIMP2 and TIMP3 were upregulated in the suprarenal AA at 4w post-coarctation compared with the other two segments and TIMP3 mRNA remained high at 8w post-coarctation. In contrast, no change in TIMP3 protein level was detected with immunoblotting after coarctation. Double immunofluorescence staining was performed to detect the cell types that express MMP9 and/or TIMP3. The results showed that MMP9 was colocalized with infiltrated macrophages in the adventitia at 4w, 8w and 12w post-coarctation. In contrast, no MMP9 was detected in VSMCs of the aortic wall. Immunoreactivity of TIMP3 was detected in the outer media and the adventitia of all AA segments of the sham group and was prominent in the vasa vasorum. Co-localization of MMP9 and TIMP3 was observed in some vasa vasorum of the distal AA segment, however, the co-localization rate was low and may not be sufficient to protect the distal AA from aneurysm progression. Overall, these results clearly showed that MMPs and TIMPs are differentially expressed during coarctation-induced AAA formation and these changes may contribute to AAA development and/or progression.

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