胰島素受體底物 1 (IRS-1)是一種訊號傳導物，而磷酸化後的 IRS-1可以當作一種蛋白質支架進而激活許多訊號傳導路徑。當IRS-1磷酸化時，它可以透過激活Rho訊號路徑以調節各種途徑，例如細胞骨架動力學，運動性，胞質分裂，細胞生長，細胞凋亡和轉錄活性。
許多研究報導指出胰島素/IRS-1可以在不同的臨床情況下促進或抑制血管新生。許多研究主張IRS-1可以促進管新生，但有一些研究則是主張IRS-1可以抑制血管新生。其中的調控機制並不清楚。血管新生是一種從原本存在的血管形成新的血管期間所發生的過程，其中包含著細胞增生、細胞遷移和管腔形成作用。所以，細胞骨架重排也涉及血管新生過程中的細胞遷移，細胞增生和管腔形成。其中，肌動蛋白是細胞骨架元素之一，所以在血管新生過程中也扮演重要的角色。
在我們的研究中，我們透過使用不同的轉染方式去建立兩種不同情況的IRS-1過度表現的細胞:模擬急性IRS-1過度表現(tIRS-1)以及慢性IRS-1過度表現(cIRS-1)。我們發現在急性表現中的tIRS-1細胞會增加細胞遷移與管腔形成能力。但相反地，在慢性IRS-1表現中的cIRS-1細胞則是會降低細胞遷移能力。這意味著急性的IRS-1過度表現會促進血管新生，但慢性的IRS-1過度表現則是會抑制血管新生。此外，我們還發現在慢性的IRS-1表現中的cIRS-1細胞透過減少β-肌動蛋白的信使核糖核酸產生來降低 β-肌動蛋白的蛋白表現量以及改變了肌動蛋白纖維的分佈。同時發現在慢性IRS-1表現中的cIRS-1細胞絲切蛋白(cofilin)的活性增加。所以我們使用絲切蛋白(cofilin)的小分子干擾核糖核酸(siRNA)來抑制絲切蛋白的表現，發現β-肌動蛋白表現量，肌動蛋白纖維的分佈與細胞遷移能力能獲得部分改善。可知IRS-1的過度表現會在不同的情況下促進或抑制血管新生，可能是透過影響肌動蛋白動力學和細胞骨架重排來調控血管新生中細胞遷移能力。

Insulin receptor substrate 1 (IRS-1) is a signal transducer and phosphorylated IRS-1 acts as a protein scaffold to activates many signaling pathways. When IRS-1
phosphorylation, it can activate various pathways, including the Rho pathway to regulate cytoskeletal dynamics, motility, cytokinesis, cell growth, apoptosis, and associated transcriptional activity.
Many studies have reported that insulin/IRS-1 can paradoxically regulate angiogenesis in different clinical situations. Several studies supported that IRS-1 promotes angiogenesis, but some studies revealed that IRS-1 inhibits angiogenesis. Angiogenesis is a process that occurs during the formation of new blood vessels from previously existing blood vessels which involves cell proliferation, cell migration, and tube formation. Among these processes of angiogenesis, cytoskeletal rearrangement plays an important role in cell migration, proliferation, and luminal formation. Actin is one of the cytoskeletal elements, and its dynamics promote cell motility, division, and vesicle trafficking.
In our study, we established two cell models: (1) acute IRS-1 overexpressed hBMEC cells by transient transfection (tIRS-1) and (2) chronic stable overexpressed hBMEC cells by building up stable clones (cIRS-1). The results showed that tIRS-1 cells increase cell migration and tube formation ability. In contrast, cIRS-1 clones decrease migration ability. The β-actin gene transcription and protein expression were reduced in cIRS-1 clones, and actin fiber distribution was disrupted. The actin polymerization regulator, cofilin, was found to increase its expression in cIRS-1 clones. After knock-down cofilin by siRNA, β-actin protein expression, the distribution of actin fibers and the cell migration ability were partially reversed in cIRS-1 clones.
In conclusion, IRS-1 overexpression can paradoxically regulate angiogenesis. It promotes angiogenesis in acute IRS-1 overexpression and inhibits angiogenesis in chronic IRS-1 overexpression. Moreover, chronic IRS-1 overexpression inhibits angiogenesis through activating cofilin, reducing β-actin gene transcription and disrupting actin dynamics.

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