Oxidative DNA damage promotes vascular ageing associated with changes in extracellular matrix-regulating proteins

Aims 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.Methods and results 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 beta 1 (TGFb1) and Collagen 4 alpha 1 in vivo compared with Ogg1KR. Foxo3a activation induced Lox, while Wnt3 induction of Wisp2 also upregulated LOX and Foxo3a, and downregulated TGF beta 1 and fibronectin 1. In humans, 8-oxo-G increased with vascular stiffness, while active OGG1 reduced with both age and stiffness.Conclusion 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. Graphical abstract Schematic illustrating changes in Ogg1, Foxo3a, Wisp2, Lox, Tgfb, and ECM proteins in vascular ageing and after Ogg1 overexpression Ageing is associated with downregulation of p300 and reduced expression and acetylation of OGG1, resulting in persistently increased oxidative DNA damage. Persistent oxidative DNA damage results in p53 activation and reduced Wisp2, resulting in reduced Foxo3a and Lox and increased Tgfb1, leading to multiple features promoting vascular stiffness. Rescue of Ogg1 expression reduces oxidative DNA damage and prevents many of these features occurring.