Receptor for Advanced Glycation End-Products Signaling Interferes with the Vascular Smooth Muscle Cell Contractile Phenotype and Function.
Receptor for Advanced Glycation End-Products Signaling Interferes with the Vascular Smooth Muscle Cell Contractile Phenotype and Function.
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DOI：
10.1371/journal.pone.0128881
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Grandbois M
中科院分区：
文献类型：
--
作者：
Simard E;Söllradl T;Maltais JS;Boucher J;D'Orléans-Juste P;Grandbois M
血糖浓度升高会促进葡萄糖和蛋白质之间的反应，形成晚期糖基化终产物（AGE）。血浆中循环的 AGE 可以激活晚期终产物受体 (RAGE)，该受体存在于内皮细胞和血管平滑肌细胞 (VSMC) 上。 RAGE 表现出复杂的信号传导，涉及小 G 蛋白和丝裂原激活蛋白激酶 (MAPK)，从而导致核因子 kappa B (NF-κB) 活性增加。虽然 RAGE 信号传导先前已在内皮细胞中得到解决，但对其对 VSMC 功能的影响知之甚少。因此，我们假设 RAGE 信号传导导致 VSMC 机械和功能特性的改变，这可能导致与糖尿病相关的并发症。我们证明 RAGE 在 A7r5 VSMC 模型中表达并发挥功能，AGE 激活 RAGE 显着增加 NF-κB 活性，已知该活性会干扰 VSMC 的收缩表型。 RAGE 激活也降低了收缩相关转录因子心肌素的蛋白水平，同时也降低了 VSMC 收缩调节因子转凝胶蛋白 (SM-22α) 的 mRNA 和蛋白水平。有趣的是，我们证明 RAGE 激活增加了整体细胞刚性，这种效应可能与肌球蛋白活性的增加有关。最后，尽管 RAGE 刺激放大了受到加压素攻击的 VSMC 中的钙信号传导和轻微的肌球蛋白活性，但它们的收缩能力受到了负面影响。总体而言，VSMC 中的 RAGE 激活可能通过改变 VSMC 的机械和功能特性来干扰 VSMC 的收缩表型，从而成为与糖尿病相关的血管疾病发展的关键。
Increased blood glucose concentrations promote reactions between glucose and proteins to form advanced glycation end-products (AGE). Circulating AGE in the blood plasma can activate the receptor for advanced end-products (RAGE), which is present on both endothelial and vascular smooth muscle cells (VSMC). RAGE exhibits a complex signaling that involves small G-proteins and mitogen activated protein kinases (MAPK), which lead to increased nuclear factor kappa B (NF-κB) activity. While RAGE signaling has been previously addressed in endothelial cells, little is known regarding its impact on the function of VSMC. Therefore, we hypothesized that RAGE signaling leads to alterations in the mechanical and functional properties of VSMC, which could contribute to complications associated with diabetes. We demonstrated that RAGE is expressed and functional in the A7r5 VSMC model, and its activation by AGE significantly increased NF-κB activity, which is known to interfere with the contractile phenotype of VSMC. The protein levels of the contraction-related transcription factor myocardin were also decreased by RAGE activation with a concomitant decrease in the mRNA and protein levels of transgelin (SM-22α), a regulator of VSMC contraction. Interestingly, we demonstrated that RAGE activation increased the overall cell rigidity, an effect that can be related to an increase in myosin activity. Finally, although RAGE stimulation amplified calcium signaling and slightly myosin activity in VSMC challenged with vasopressin, their contractile capacity was negatively affected. Overall, RAGE activation in VSMC could represent a keystone in the development of vascular diseases associated with diabetes by interfering with the contractile phenotype of VSMC through the modification of their mechanical and functional properties.