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

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Genetics

Background:

• Vascular ageing is characterized by vessel stiffening due to extracellular matrix (ECM) protein deposition.
• Oxidative DNA damage is implicated in vascular ageing, but its regulatory role in ECM proteins and vascular stiffening remains unclear.

Purpose of the Study:

• To determine the relationship between oxidative DNA damage and ECM regulatory proteins in the context of vascular ageing.

Main Methods:

• Examined oxidative DNA damage, base excision repair (BER) enzyme 8-Oxoguanine DNA Glycosylase (Ogg1) and its regulators, aging markers, and ECM proteomics in mice.
• Assessed vascular stiffness in vivo using control, Ogg1 knockout, and Ogg1-expressing mice.
• Investigated the effects of Ogg1 overexpression on ECM regulatory proteins in vitro and in vivo.

Main Results:

• Vascular ageing in mice correlated with increased oxidative DNA damage and decreased Ogg1 expression and activity.
• Ogg1 deficiency exacerbated vascular stiffness, while Ogg1 expression normalized arterial compliance and distensibility.
• ECM proteomics revealed age-related changes in collagens and downregulation of lysyl oxidase (LOX) and WISP2; Ogg1 overexpression upregulated LOX and WISP2.

Conclusions:

• Vascular ageing involves oxidative DNA damage, reduced BER protein expression, and altered ECM proteins.
• Ogg1 plays a protective role against vascular ageing by modulating ECM regulatory proteins like LOX and WISP2.