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

Kirsty Foote; Marieke Rienks; Lukas Schmidt; Konstantinos Theofilatos; Yasmin; Matiss Ozols; Alexander Eckersley; Aarti Shah; Nichola Figg; Alison Finigan; Kevin O'Shaughnessy; Ian B Wilkinson; Manuel Mayr; Martin Bennett

doi:10.1093/cvr/cvae091

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

Cardiovasc Res. 2024 May 8:cvae091. doi: 10.1093/cvr/cvae091. Online ahead of print.

Affiliations

¹ Section of Cardiorespiratory Medicine, University of Cambridge, Victor Phillip Dahdaleh Heart & Lung Research Institute, Papworth Road, Cambridge Biomedical Campus, Cambridge, CB2 0BB.
² Cardiovascular Division, King's College London, The James Black Centre, 2nd Floor, 125 Coldharbour Lane, SE5 9NU, London.
³ Experimental Medicine and Therapeutics, Department of Medicine, University of Cambridge. Box 157, Cambridge Biomedical Campus, Cambridge, CB2 2QQ.
⁴ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Saffron Walden, CB10 1RQ.
⁵ Division of Musculoskeletal & Dermatological Sciences, University of Manchester, First Floor, Core Technology Facility, 46 Grafton St, Manchester, M13 9NT.

PMID: 38717632
DOI: 10.1093/cvr/cvae091

Abstract

Aims: Vascular aging is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular aging, 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 aging.

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 aging, and ECM proteomics in mice from 22-72w. Vascular aging 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 normalised all parameters to 72w. ECM proteomics identified major changes in collagens with aging, 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.

Conclusions: Vascular aging is associated with oxidative DNA damage, downregulation of major BER proteins, and changes in multiple ECM structural and regulatory proteins. Ogg1 protects against vascular aging, associated with changes in ECM regulatory proteins including LOX and WISP2.