Abstract
Defective Base Excision Repair of Oxidative DNA Damage in Vascular Smooth Muscle Cells Promotes Atherosclerosis
Highlights
Atherosclerotic plaques demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine (8oxoG) lesions. 8oxoG is repaired by base excision repair enzymes; the mechanisms regulating 8oxoG accumulation in vascular smooth muscle cells (VSMCs) and its effects on their function and in atherosclerosis are unknown
We demonstrate that human atherosclerosis exhibits increased oxidative DNA damage and defective repair of that damage in vascular smooth muscle cells (VSMCs)
8-Oxoguanine DNA glycosylase is a major base excision repair enzyme in VSMCs, the activity and protein stability of which are regulated by acetylation through the p300 acetyltransferase and sirtuin 1 deacetylase enzymes
Summary
We studied levels of 8oxoG and its regulatory enzymes in human atherosclerosis, the mechanisms regulating 8oxoG repair and the base excision repair enzyme 8oxoG DNA glycosylase I (OGG1) in VSMCs in vitro, and the effects of reducing 8oxoG in VSMCs in atherosclerosis in ApoE−/− mice. Human tissue was obtained under informed consent with protocols approved by the Cambridge or Huntingdon Research. Atherosclerotic plaques and normal aorta were obtained from separate patients undergoing carotid endarterectomy or aortic valve replacement, respectively. Cell death was determined with an apoptosis detection kit (BD BioSciences) as described in the online-only Data Supplement. All in vivo experiments followed UK Home Office licensing and were approved by the local animal ethics committee. Transgenic mice were generated as described in the online-only Data Supplement. The global OGG−/− and SM22α-SIRT1ex4/ex[4] conditional transgenic mouse models were generated as described previously.[9,10] OGG1−/− mouse embryos were a gift from Christi Walter (University of Texas Health Science Center, Houston, TX)
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