Foote Kirsty, Rienks Marieke, Schmidt Lukas, Theofilatos Konstantinos, Ozols Matiss, Eckersley Alexander, Shah Aarti, Figg Nichola, Finigan Alison, O'Shaughnessy Kevin, Wilkinson Ian, Mayr Manuel, Bennett Martin
Section of Cardiorespiratory Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute, Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0BB, UK.
Cardiovascular Division, King's College London, The James Black Centre, 2nd Floor, 125 Coldharbour Lane, London SE5 9NU, UK.
Cardiovasc Res. 2025 May 6;121(4):614-628. doi: 10.1093/cvr/cvae091.
Vascular ageing is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular ageing, but how it regulates ECM proteins and vascular stiffening is unknown. We sought to determine the relationship between oxidative DNA damage and ECM regulatory proteins in vascular ageing.
We examined oxidative DNA damage, the major base excision repair (BER) enzyme 8-Oxoguanine DNA Glycosylase (Ogg1) and its regulators, multiple physiological markers of ageing, and ECM proteomics in mice from 22 to 72 w. Vascular ageing was associated with increased oxidative DNA damage, and decreased expression of Ogg1, its active acetylated form, its acetylation regulatory proteins P300 and CBP, and the transcription factor Foxo3a. Vascular stiffness was examined in vivo in control, Ogg1-/-, or mice with vascular smooth muscle cell-specific expression of Ogg1+ (Ogg1) or an inactive mutation (Ogg1KR). Ogg1-/- and Ogg1KR mice showed reduced arterial compliance and distensibility, and increased stiffness and pulse pressure, whereas Ogg1 expression normalized all parameters to 72 w. ECM proteomics identified major changes in collagens with ageing, and downregulation of the ECM regulatory proteins Protein 6-lysyl oxidase (LOX) and WNT1-inducible-signaling pathway protein 2 (WISP2). Ogg1 overexpression upregulated LOX and WISP2 both in vitro and in vivo, and downregulated Transforming growth factor β1 (TGFb1) and Collagen 4α1 in vivo compared with Ogg1KR. Foxo3a activation induced Lox, while Wnt3 induction of Wisp2 also upregulated LOX and Foxo3a, and downregulated TGFβ1 and fibronectin 1. In humans, 8-oxo-G increased with vascular stiffness, while active OGG1 reduced with both age and stiffness.
Vascular ageing is associated with oxidative DNA damage, downregulation of major BER proteins, and changes in multiple ECM structural and regulatory proteins. Ogg1 protects against vascular ageing, associated with changes in ECM regulatory proteins including LOX and WISP2.
血管老化的特征是血管硬化，细胞外基质（ECM）蛋白（包括胶原蛋白）沉积增加。氧化DNA损伤发生在血管老化过程中，但它如何调节ECM蛋白和血管硬化尚不清楚。我们试图确定血管老化过程中氧化DNA损伤与ECM调节蛋白之间的关系。
我们检测了22至72周龄小鼠的氧化DNA损伤、主要碱基切除修复（BER）酶8-氧代鸟嘌呤DNA糖基化酶（Ogg1）及其调节因子、多种衰老生理标志物和ECM蛋白质组学。血管老化与氧化DNA损伤增加、Ogg1及其活性乙酰化形式、其乙酰化调节蛋白P300和CBP以及转录因子Foxo3a的表达降低有关。在对照组、Ogg1基因敲除小鼠、血管平滑肌细胞特异性表达Ogg1+（Ogg1）或无活性突变（Ogg1KR）的小鼠体内检测血管硬度。Ogg1基因敲除小鼠和Ogg1KR小鼠的动脉顺应性和扩张性降低，硬度和脉压增加，而Ogg1表达使所有参数在72周时恢复正常。ECM蛋白质组学确定了随着衰老胶原蛋白的主要变化，以及ECM调节蛋白6-赖氨酸氧化酶（LOX）和WNT1诱导信号通路蛋白2（WISP2）的下调。与Ogg1KR相比，Ogg1过表达在体外和体内均上调了LOX和WISP2，并在体内下调了转化生长因子β1（TGFb1）和胶原蛋白4α1。Foxo3a激活诱导Lox，而Wnt3诱导Wisp2也上调了LOX和Foxo3a，并下调了TGFβ1和纤连蛋白1。在人类中，8-氧代鸟嘌呤随着血管硬度增加，而活性OGG1随着年龄和硬度降低。
血管老化与氧化DNA损伤、主要BER蛋白下调以及多种ECM结构和调节蛋白的变化有关。Ogg1可预防血管老化，这与包括LOX和WISP2在内的ECM调节蛋白的变化有关。
