主動脈瘤是一種慢性心血管疾病會造成血管破裂而致死。血管有不正常膨大的現象為主要的病理特徵。主動脈瘤可發生在動脈的任何部位，臨床上好發於腹及胸主動脈。因大部分患者無不適症狀，通常為其他原因檢查而偶然被診斷。先前的研究發現基質細胞蛋白CCN1會在疾病或受損組織中表現，並透過結合不同整合素受器來調控細胞。CCN1在主動脈瘤中可能扮演的生理角色仍不清楚，本研究假設CCN1會在主動脈瘤發生時受激發表達並透過其接受器整合素α6β1促進主動脈瘤生成。為測試CCN1在主動脈瘤中的角色，我們利用angiotensin II (Ang II)刺激主動脈瘤的小鼠模式，以Apoe-/-Ccn1+/LacZ小鼠觀察表現CCN1的位置與細胞種類，並以Apoe-/-CCN1dm/dm小鼠，利用其帶有兩序列突變而使CCN1蛋白選擇性無法結合整合素α6β1，來探討CCN1在主動脈瘤中之影響。在Ang II處理下，Apoe-/-CCN1+/LacZ小鼠在經過X-gal染色後，可以明顯發現CCN1之表現量在主動脈顯著上升，並在結構較破損的地方，有更多CCN1之表現量，顯示CCN1在此動脈瘤中可能為一重要因子。而在同樣處理下，Apoe-/-小鼠在好發動脈瘤的腹主動脈中，平滑肌細胞明顯流失，血管壁中彈性膜破碎斷裂。相對的，Apoe-/-CCN1dm/dm小鼠腹主動脈有正常的平滑肌細胞組成，及結構完整的彈性膜層。此結果顯示阻斷CCN1與α6β1結合可以減緩動脈瘤的發展，顯示CCN1在主動脈瘤中扮演重要的角色，可發展為新的治療標的。

Aortic aneurysm (AA) is a chronic vascular disease which may cause sudden death upon aortic rupture. The dilating arterial wall is a distinct feature of AA. Because AA is asymptomatic at earlier stages, it is often detected unexpectedly. The extracellular protein CCN1 is a secreted protein that regulates multiple cell functions. CCN1 is induced in tissue injury and pathological conditions often through binding to its integrin receptor α6β1 to increase oxidative stress, inflammatory responses, and matrix remodeling, which are also the driving forces for the progression of AA. We hypothesized that CCN1 may be induced to promote the progression of AA through integrin α6β1. To test this hypothesis, first we preformed the angiotensin II (Ang II)-induced AA mouse model in Apoe-/-CCN1+/LacZ mice to study the expression of CCN1. An osmotic pumps filled with Ang II (1 μg/kg/min) was implanted subcutaneously into Apoe-/-CCN1+/LacZ mice for 14 days. We found that Ang II induced CCN1 expression (reflected by the LacZ activity) in the aorta. To investigate the function of CCN1 through integrin α6β1, we used the α6β1-binding-defective CCN1 mutant (CCN1dm/dm) mice in the Ang II model. We found aortic dilation and smooth muscle cell loss in Apoe-/- mice receiving Ang II treatment, while Apoe-/-CCN1dm/dm mice displayed resistance to Ang II-induced aneurysm in the abdominal aorta. These data indicated that CCN1 promotes the progression of AA and SMC through binding to α6β1. Our results support to use CCN1 as a new therapeutic target for AA.

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