氮氧化物4
氮氧化物1
活性氧
内科学
NADPH氧化酶
内分泌学
骨保护素
阿普辛尼
血管平滑肌
化学
一氧化氮
内皮功能障碍
血管紧张素II
生物化学
生物
医学
受体
激活剂(遗传学)
平滑肌
作者
Rhéure Alves-Lopes,Karla B Neves,Anastasiya Strembitska,Adam Harvey,Katie Harvey,Hiba Yusuf,Susan Haniford,R Hepburn,Jennifer Dyet,Wendy Beattie,Laura Haddow,John McAbney,Delyth Graham,Augusto C. Montezano
出处
期刊:Clinical Science
[Portland Press]
日期:2021-10-01
卷期号:135 (20): 2429-2444
被引量:6
摘要
Abstract Osteogenic factors, such as osteoprotegerin (OPG), are protective against vascular calcification. However, OPG is also positively associated with cardiovascular damage, particularly in pulmonary hypertension, possibly through processes beyond effects on calcification. In the present study, we focused on calcification-independent vascular effects of OPG through activation of syndecan-1 and NADPH oxidases (Noxs) 1 and 4. Isolated resistance arteries from Wistar–Kyoto (WKY) rats, exposed to exogenous OPG, studied by myography exhibited endothelial and smooth muscle dysfunction. OPG decreased nitric oxide (NO) production, eNOS activation and increased reactive oxygen species (ROS) production in endothelial cells. In VSMCs, OPG increased ROS production, H2O2/peroxynitrite levels and activation of Rho kinase and myosin light chain. OPG vascular and redox effects were also inhibited by the syndecan-1 inhibitor synstatin (SSNT). Additionally, heparinase and chondroitinase abolished OPG effects on VSMCs-ROS production, confirming syndecan-1 as OPG molecular partner and suggesting that OPG binds to heparan/chondroitin sulphate chains of syndecan-1. OPG-induced ROS production was abrogated by NoxA1ds (Nox1 inhibitor) and GKT137831 (dual Nox1/Nox4 inhibitor). Tempol (SOD mimetic) inhibited vascular dysfunction induced by OPG. In addition, we studied arteries from Nox1 and Nox4 knockout (KO) mice. Nox1 and Nox4 KO abrogated OPG-induced vascular dysfunction. Vascular dysfunction elicited by OPG is mediated by a complex signalling cascade involving syndecan-1, Nox1 and Nox4. Our data identify novel molecular mechanisms beyond calcification for OPG, which may underlie vascular injurious effects of osteogenic factors in conditions such as hypertension and/or diabetes.
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