Soluble RAGE attenuates AngII-induced endothelial hyperpermeability by disrupting HMGB1-mediated crosstalk between AT1R and RAGE

Autor: Sungha Park, Jiye Lee, Soyeon Lim, Miran Seo, Soyoung Cho, Soyoung An, Myungeun Lee, Nara Yoon, Jisu Jeong, Juyeon Lim
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Experimental and Molecular Medicine, Vol 51, Iss 9, Pp 1-15 (2019)
Experimental & Molecular Medicine
ISSN: 2092-6413
1226-3613
Popis: Increased endothelial permeability, one of the earliest signs of endothelial dysfunction, is associated with the development of cardiovascular diseases such as hypertension and atherosclerosis. Recent studies suggest that the receptor for advanced glycation end products (RAGE) regulates endothelial permeability in inflammation. In the present study, we investigated the regulatory mechanism of RAGE in endothelial hyperpermeability induced by angiotensin II (Ang II), a well-known inflammatory mediator, and the potential therapeutic effect of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands. For in vitro studies, Ang II-treated human umbilical vein endothelial cells (HUVECs) were treated with siRNA specific to either RAGE or sRAGE to disrupt RAGE-mediated signaling. Endothelial permeability was estimated using FITC-labeled dextran 40 and a resistance meter. To evaluate intercellular junction disruption, VE-cadherin expression was examined by western blotting and immunocytochemistry. Ang II increased the expression of the Ang II type 1 receptor (AT1R) and RAGE, and this increase was inhibited by sRAGE. sRAGE prevented Ang II-induced VE-cadherin disruption in HUVECs. For in vivo studies, Ang II-infused, atherosclerosis-prone apolipoprotein E knockout mice were utilized. Endothelial permeability was assessed by Evans blue staining of the aorta. Ang II increased endothelial barrier permeability, and this effect was significantly attenuated by sRAGE. Our data demonstrate that blockade of RAGE signaling using sRAGE attenuates Ang II-induced endothelial barrier permeability in vitro and in vivo and indicate the therapeutic potential of sRAGE in controlling vascular permeability under pathological conditions.
Cardiovascular disease: Decoy protein improves blood vessel function A decoy version of a protein involved in regulating the leakiness of blood vessels can help ameliorate vascular problems that lead to high blood pressure and plaque deposition in the arteries. A team from South Korea led by Soyeon Lim from Catholic Kwandong University in Gangneung and Sungha Park from Yonsei University College of Medicine in Seoul induced hyper-permeability in both human vein cells and atherosclerosis-prone mice. They then blocked signaling through a membrane-bound protein called RAGE, a receptor that helps boost vessel permeability by using a soluble version of this same protein. In both the human cells and mouse models, this free-floating RAGE bound and blocked the receptor’s normal activator, leading to suppressed permeability and improved function of the blood vessel lining. This decoy strategy holds therapeutic promise for people prone to cardiovascular disease.
Databáze: OpenAIRE
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