Role of DNA damage in atherosclerosis—Bystander or participant?

Gray, Kelly; Bennett, Martin R.

doi:10.1016/j.bcp.2011.06.025

Cited by 52 publications

(40 citation statements)

References 89 publications

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“…For example, DNA damage induced by radiotherapy can either enhance or inhibit atherosclerosis and neointima formation in human or animal arteries. 2 Some genetic diseases associated with DNA damage, such as HutchisonGilford Progeria and Werner syndromes show enhanced atherosclerosis, 16,17 but many others do not. 2 Similarly, genetic or pharmacological targeting of the DDR either inhibits or enhances atherosclerosis.…”

Section: Dna Damage In Atherosclerosis 817mentioning

confidence: 99%

“…2 Some genetic diseases associated with DNA damage, such as HutchisonGilford Progeria and Werner syndromes show enhanced atherosclerosis, 16,17 but many others do not. 2 Similarly, genetic or pharmacological targeting of the DDR either inhibits or enhances atherosclerosis. 18,19 Finally, whether these extensive experimental or natural germline changes recapitulate more modest DNA damage seen in human atherosclerosis is unclear.…”

Section: Dna Damage In Atherosclerosis 817mentioning

confidence: 99%

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Effects of DNA Damage in Smooth Muscle Cells in Atherosclerosis

Gray

Kumar

Figg

et al. 2015

Circulation Research

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Rationale: DNA damage and the DNA damage response have been identified in human atherosclerosis, including in vascular smooth muscle cells (VSMCs). However, although double-stranded breaks (DSBs) are hypothesized to promote plaque progression and instability, in part, by promoting cell senescence, apoptosis, and inflammation, the direct effects of DSBs in VSMCs seen in atherogenesis are unknown. Objective: To determine the presence and effect of endogenous levels of DSBs in VSMCs on atherosclerosis. Methods and Results: Human atherosclerotic plaque VSMCs showed increased expression of multiple DNA damage response proteins in vitro and in vivo, particularly the MRE11/RAD50/NBS1 complex that senses DSB repair. Oxidative stress–induced DSBs were increased in plaque VSMCs, but DSB repair was maintained. To determine the effect of DSBs on atherosclerosis, we generated 2 novel transgenic mice lines expressing NBS1 or C-terminal deleted NBS1 only in VSMCs, and crossed them with apolipoprotein E −/− mice. SM22α-NBS1/apolipoprotein E −/− VSMCs showed enhanced DSB repair and decreased growth arrest and apoptosis, whereas SM22α-(ΔC)NBS1/apolipoprotein E −/− VSMCs showed reduced DSB repair and increased growth arrest and apoptosis. Accelerating or retarding DSB repair did not affect atherosclerosis extent or composition. However, VSMC DNA damage reduced relative fibrous cap areas, whereas accelerating DSB repair increased cap area and VSMC content. Conclusions: Human atherosclerotic plaque VSMCs show increased DNA damage, including DSBs and DNA damage response activation. VSMC DNA damage has minimal effects on atherogenesis, but alters plaque phenotype inhibiting fibrous cap areas in advanced lesions. Inhibiting DNA damage in atherosclerosis may be a novel target to promote plaque stability.

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Section: Dna Damage In Atherosclerosis 817mentioning

confidence: 99%

Section: Dna Damage In Atherosclerosis 817mentioning

confidence: 99%

Effects of DNA Damage in Smooth Muscle Cells in Atherosclerosis

Gray

Kumar

Figg

et al. 2015

Circulation Research

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“…18,41 Physiological hair greying is caused by defective renewal of melanocyte stem cells, which has been suggested to be caused by accumulation of DNA damage associated with aging. 42 Because DNA damage may also be a causal factor in atherosclerosis, 43 greying of hair may be a marker of susceptibility to atherosclerosis and possibly other age-related diseases. In the present study, greying of hair did not associate with risk of IHD or MI after multifactorial adjustment, although in the 12-year follow-up of the same study, an association with myocardial infarction was found in men.…”

Section: Comparison With Other Studiesmentioning

confidence: 99%

Visible Age-Related Signs and Risk of Ischemic Heart Disease in the General Population

et al. 2014

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Background-Cardiovascular disease is 1 of the most common age-related diseases, and also 1 of the most common causes of death in the general population. We tested the hypothesis that visible age-related signs associate with risk of ischemic heart disease (IHD), myocardial infarction (MI), and death in the general population, independent of chronological age. Methods and Results-10,885 individuals aged 20 to 93 years free of IHD were followed from 1976 through 1978 until June 2011 with 100% complete follow-up. During these 35 years of follow-up, 3401 participants developed IHD and 1708 developed MI. Presence of frontoparietal baldness, crown top baldness, earlobe crease, and xanthelasmata was associated with increased risk of IHD or MI after multifactorial adjustment for chronological age and well-known cardiovascular risk factors. The risk of IHD and MI increased stepwise with increasing number of age-related signs with multifactorially adjusted hazard ratios up to 1.40 (95% confidence interval, 1.20-1.62) for IHD and 1.57 (1.28-1.93) for MI, in individuals with 3 to 4 versus no age-related signs at baseline (P for trend <0.001). In all age groups in both women and men, absolute 10-year risk of IHD and MI increased with increasing number of visible age-related signs. Conclusions-Male pattern baldness, earlobe crease, and xanthelasmata-alone or in combination-associate with increased risk of ischemic heart disease and myocardial infarction independent of chronological age and other wellknown cardiovascular risk factors. This is the first prospective study to show that looking old for your age is a marker of poor cardiovascular health. (Circulation. 2014;129:990-998.)

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“…Апоптоз ГМК увеличивает атерогенез, прогрессию и нестабильность атеросклеротических бляшек [32]. Следует отметить, что кроме клеток артерий маркеры повреждения и репарации ДНК идентифицированы в лейкоцитах периферической крови больных атеро-склерозом и они коррелируют с факторами риска и степенью тяжести атеросклероза, а также развитием острых сосудистых событий [33,34].…”

Section: российскийunclassified