主動脈瘤 (AA)是一種以細胞外基質退化疾病，其特徵為主動脈的內徑擴大到正常的1.5倍。其無症狀的特性使病人不能及早發現而導致血管破裂因而死亡率相當之高，目前也尚無有效的預防或治療方法。CCN1 (Cellular communication network factor 1) 是一種分泌性基質細胞蛋白，透過結合多種整合素來發揮作用，使其在不同類型的細胞中發揮不同的活性。我們實驗室先前的研究表明CCN1會在Angiotensin II (Ang II)誘導的AA小鼠模型的病變區域被大量誘導，但CCN1在AA中扮演的角色尚未被釐清。影響血管構造完整性的關鍵因素之一是血管平滑肌細胞(vascular smooth muscle cells)的狀態。此種細胞可以因應刺激變換為不同的表型，此過程也被稱為VSMC表型轉換 (phenotypic switching)，並在AA的發展中起到相當重要的作用。我們假設CCN1會透過與整合素α6β1結合來誘導VSMCs進入降解表型，進而促進AA的發展。為測試這個假說，我們利用Ang II輸注4週來刺激小鼠產生AA，並利用攜帶CCN1-dm (無法與α6β1結合之突變CCN1)的 Apoe-/-Ccn1dm/dm 小鼠來測試阻斷CCN1與α6β1結合是否影響AA的發展。結果顯示Apoe-/-Ccn1dm/dm組的主動脈直徑與其管腔內徑都較不受Ang II刺激而增大，主動脈結構相對完整且巨噬細胞浸潤也較少，顯示CCN1促進AA發展的角色。在大鼠原代VSMCs細胞研究中透過專一性阻斷 CCN1和α6β1之間結合的T1 peptide來探討CCN1在Ang II刺激的VSMC表型轉變中所扮演的角色。西方墨點法中顯示Ang II會誘導VSMCs中CCN1、KLF4、MMP12 和IL-6的表達上升，其中KLF4為已知促VSMC去分化的早期因子。而在經T1阻斷CCN1作用後發現也可有效抑制KLF4及降解表型相關因子，表明CCN1在VSMC表型轉換中有著十分上游且關鍵的作用。我們目前仍持續探索CCN1/α6β1訊息傳遞如何影響KLF4表達，進而引發VSMC表型轉換。總結我們目前的結果表明，CCN1透過與α6β1結合誘導ECM重塑和VSMC表型轉換而導致AA的惡化，也使CCN1成為一個治療AA的嶄新目標。

Aortic aneurysm (AA) is a disease characterized by the degeneration of the extracellular matrix (ECM), leading to dilation of the aorta. Its asymptomatic progression results in high mortality rates, and currently, there is no effective prevention or treatment available. Cellular communication network factor 1 (CCN1) is a secreted matricellular protein that functions through multiple integrin receptors to exert diverse activities in different cell types. Our preliminary results showed that CCN1 was induced in the lesion areas of the Angiotensin II (Ang II)-induced AA mouse model. One of the key factors involved in maintaining vessel integrity is the state of vascular smooth muscle cells (VSMCs), and VSMC phenotypic switching plays a crucial role in AA development. We hypothesized that CCN1 mediates AA progression by inducing VSMCs to adopt a degradative phenotype through integrins α6β1. To assess the role of CCN1, Apoe-/-Ccn1dm/dm mice, carrying the α6β1-binding-deficient mutant CCN1-dm, were used in the Ang II-induced AA mouse model. The aortae were harvested after 4-week Ang II infusion. After treatment, the Apoe-/- Ccn1dm/dm group showed less aortic dilatation and deformation, smaller maximal-diameters, and narrower lumen comparing with Apoe-/-Ccn1+/+ mice. The Apoe-/- Ccn1dm/dm mice maintained better aortic wall integrity and exhibited less macrophage infiltration. In vitro studies, the antagonistic T1 peptide was used to specifically block the binding between CCN1 and α6β1 to study the regulation of VSMC phenotypic changes by CCN1 upon Ang II treatments in the rat primary aortic VSMCs. Western blotting showed that Ang II induced the expression of CCN1, KLF4, MMP12 and IL-6 in VSMCs. KLF4 is known to initiate VSMC dedifferentiation. Blocking CCN1 with T1 inhibited KLF4 induction and degradative phenotype-associated factors, suggesting a critical role of CCN1 in VSMC phenotype switching. How CCN1/α6β1 signaling regulates KLF4 expression and VSMC phenotypic switching remains to be determined. Our results show that CCN1 induces ECM remodeling and VSMC phenotypic switching through binding to α6β1, resulting in AA progression. This finding may establish CCN1 as a novel therapeutic target for AA.

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