Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, People's Republic of China.
Vascular Center of Shanghai JiaoTong University, Shanghai, People's Republic of China.
Clin Sci (Lond). 2018 Jan 19;132(2):213-229. doi: 10.1042/CS20171273. Print 2018 Jan 31.
Ongoing efforts to remove pathological inflammatory stimuli are crucial for the protection of endothelial cells in diabetes. Nerve injury-induced protein 1 (Ninj1) is an adhesion molecule that not only contributes to inflammation but also regulates the apoptosis of endothelial cells. In the present study, Ninj1 was found highly expressed in endothelial cells in Type 2 diabetic mice and increased in high-glucose (HG) cultured HUVECs. Furthermore, we found that Ninj1 levels are up-regulated in endothelial cells in clinical specimens of diabetic patients when compared with nondiabetic tissues, indicating a biological correlation between Ninj1 and endothelial pathophysiology in diabetic condition. Functional blocking of Ninj1 promoted endothelial tube formation and eNOS phosphorylation in the HG condition. Additionally, blocking Ninj1 inhibited the activation of caspase-3 and increased the Bcl-2/Bax ratio, thus inhibiting HUVECs apoptosis induced by HG. HG-induced ROS overproduction, p38 MAPK and NF-κB activation, and the overexpression of , and genes were ameliorated after Ninj1 was blocked. Using the signaling pathway inhibitor LY294002, we found that Bcl-2 expression and eNOS phosphorylation after Ninj1 blockade were regulated via PI3K/Akt signaling pathway. The endothelial contents, α-SMAPECAM-1 vascular numbers, and blood perfusion in the hindlimb were markedly up-regulated after Ninj1 was blocked. According to our findings, functional blocking of Ninj1 shows protective effects on diabetic endothelial cells both and Thus, we consider Ninj1 to be a potential therapeutic target for preventing endothelial dysfunction in diabetes mellitus.
持续努力消除病理性炎症刺激对于保护糖尿病中的内皮细胞至关重要。神经损伤诱导蛋白 1（Ninj1）是一种黏附分子，不仅有助于炎症反应，还调节内皮细胞的凋亡。在本研究中，发现 Ninj1 在 2 型糖尿病小鼠的内皮细胞中高度表达，并在高糖（HG）培养的 HUVECs 中增加。此外，我们发现与非糖尿病组织相比，糖尿病患者的内皮细胞中 Ninj1 水平升高，表明 Ninj1 与糖尿病状态下的内皮病理生理学之间存在生物学相关性。在 HG 条件下，Ninj1 的功能阻断促进了内皮细胞管形成和 eNOS 磷酸化。此外，阻断 Ninj1 抑制了 caspase-3 的激活，增加了 Bcl-2/Bax 比值，从而抑制了 HG 诱导的 HUVECs 凋亡。阻断 Ninj1 后，HG 诱导的 ROS 过度产生、p38 MAPK 和 NF-κB 激活以及 、 和 基因的过表达得到改善。使用信号通路抑制剂 LY294002，我们发现 Ninj1 阻断后 Bcl-2 表达和 eNOS 磷酸化是通过 PI3K/Akt 信号通路调节的。阻断 Ninj1 后，α-SMAPECAM-1 血管数量和后肢血流明显增加。根据我们的发现，Ninj1 的功能阻断对糖尿病内皮细胞具有保护作用，因此，我们认为 Ninj1 是预防糖尿病内皮功能障碍的潜在治疗靶点。
