Loss of Heterozygosity and Microsatellite Instability in Human Atherosclerotic Plaques

doi:10.1006/bbrc.1996.1151

Biochemical and Biophysical Research Communications

Volume 225, Issue 1, 5 August 1996, Pages 186-190

https://doi.org/10.1006/bbrc.1996.1151 Get rights and content

Abstract

Several lines of evidence suggest that mutation events may be involved in the development of atherosclerosis. The aim of the present investigation was to perform an allelotype analysis in 30 atherosclerotic lesions in order to reveal any deletions involved in the development of the disease. Eighteen chromosomal arms were tested by one microsatellite marker located on each arm and allelic imbalance in at least one marker was observed in 7 (23%) cases. Furthermore, the analysis revealed the presence of microsatellite instability (MI) in 10 (33%) cases, suggesting that an increase in the mutation rate may be involved in the formation of the plaque. These results highlight the mutation concept for the atherogenesis and suggest that LOH and MI may be involved in the development of the disease.

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While the age-related accumulation of DNA breaks and DNA adducts have not been shown in human vascular cells, DNA breaks have been shown to occur with advancing age in sperm cells [182] and the mitochondrial DNA of skeletal muscle [183,184]. Microsatellite instability and loss of heterozygosity, which is thought to be a consequence of DNA breaks, has been linked to pulmonary artery hypertension [185] and atherosclerosis [186–191] in humans. Interestingly, two recently developed mouse models of disrupted DNA adduct repair (xeroderma pigmentosum D (XPD)ttd and ERCC1d/− mice) demonstrated age-related impairments in EDD in response to acetylcholine, reduced eNOS expression and activity, and increased p53 expression and ROS content [192].
Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction results from a reduction in nitric oxide bioavailability downstream of endothelial oxidative stress and inflammation that can be further modulated by traditional CVD risk factors in older adults. Greater endothelial oxidative stress with aging is a result of augmented production from the intracellular enzymes NADPH oxidase and uncoupled eNOS, as well as from mitochondrial respiration in the absence of appropriate increases in antioxidant defenses as regulated by relevant transcription factors, such as FOXO. Interestingly, it appears that NFkB, a critical inflammatory transcription factor, is sensitive to this age-related endothelial redox change and its activation induces transcription of pro-inflammatory cytokines that can further suppress endothelial function, thus creating a vicious feed-forward cycle. This review will discuss the two macro-mechanistic processes, oxidative stress and inflammation, that contribute to endothelial dysfunction with advancing age as well as the cellular and molecular events that lead to the vicious cycle of inflammation and oxidative stress in the aged endothelium. Other potential mediators of this pro-inflammatory endothelial phenotype are increases in immune or senescent cells in the vasculature. Of note, genomic instability, telomere dysfunction or DNA damage has been shown to trigger cell senescence via the p53/p21 pathway and result in increased inflammatory signaling in arteries from older adults. This review will discuss the current state of knowledge regarding the emerging concepts of senescence and genomic instability as mechanisms underlying oxidative stress and inflammation in the aged endothelium. Lastly, energy sensitive/stress resistance pathways (SIRT-1, AMPK, mTOR) are altered in endothelial cells and/or arteries with aging and these pathways may modulate endothelial function via key oxidative stress and inflammation-related transcription factors. This review will also discuss what is known about the role of “energy sensing” longevity pathways in modulating endothelial function with advancing age. With the growing population of older adults, elucidating the cellular and molecular mechanisms of endothelial dysfunction with age is critical to establishing appropriate and measured strategies to utilize pharmacological and lifestyle interventions aimed at alleviating CVD risk. This article is part of a Special Issue entitled “SI: CV Aging”.
The role of DNA damage and repair in atherosclerosis: A review
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It has been proposed that oxidative stress decreased anti-oxidant level and reduced DNA repair efficiency can contribute to progressive atherosclerotic coronary disease [10]. Human studies have demonstrated a differential expression of MSI and LOH in atherosclerotic lesions compared to normal vascular tissue [11]. Macro-damage in the form of increased rates of trisomy 7 and monosomy of chromosome 11 was found in a small study examining unstable atherosclerotic plaques [12].
The global burden of cardiovascular disease is increasing despite therapeutic advances in medication and interventional technologies. Accumulated deoxyribonucleic acid (DNA) damage and subsequent repair pathways are now increasingly recognised as a causal factor in the initiation and progression of atherosclerosis. These molecular alterations have been shown to occur within affected vasculature, plaque microenvironment as well as in circulating cells. The DNA damage response (DDR) pathway is reliant on post-translational modification of sensing proteins which activate a signalling cascade to repair, if possible, DNA damaged sites in response to various environmental and physiological insults. This review summarises the current evidence for DNA damage in atherosclerosis, the key steps involved in the DDR pathway, DNA repair and their subsequent effects on atherosclerotic plaques, as well as the therapeutic options in managing DNA damage-induced atherosclerosis.
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The increasing use of medical imaging in cardiology practice, especially with increasing utilization of nuclear cardiology, mandates the importance of awareness of cardiac toxicity from radiological imaging. Radiation can be ionizing from X-ray or computed tomography (CT) or nonionizing from magnetic resonance imaging (MRI). Ionizing radiation can alter the structure of cells and induce cell damage; however, nonionizing radiation does not. Cardiologists are exposed to more radiation during procedures such as pacemaker implants, angiogram, and electrophysiological studies. There are strategies to minimize the exposure to radiation and one among them is the ALARA principle. It is vital for physicians to be aware of the radiation-induced effects, and it is important to routinely employ them in practice to reduce radiation-induced hazards.
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Some epidemiological and experimental data are clearly in favour of an increased cardiovascular risk associated with exposure to low doses. However, given the multifactorial origin of cardiovascular diseases and the lack of a clear pathophysiologic mechanism, epidemiological results have to be carefully interpreted. Further research should be conducted in this area.
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Cette revue concerne des populations variées, telles que les survivants des explosions atomiques, travailleurs du nucléaire, liquidateurs de Tchernobyl, médecins, personnels navigants et personnes soumises aux rayonnements ionisants d’origine médicale.
Parmi les 27 études analysant globalement le risque cardiovasculaire, un excès lié aux radiations a pu être mis en évidence pour 13 d’entre elles. Les études étudiant le risque cardiaque ischémique retrouvaient une association avec la dose dans sept études sur les 16 analysées. Le risque cérébrovasculaire était significativement augmenté dans cinq études sur les 12 considérées.
Certaines données épidémiologiques et expérimentales sont clairement en faveur d’un risque cardiovasculaire lié aux irradiations à des faibles doses. Cependant, en raison du caractère multifactoriel des pathologies cardiovasculaires et en l’absence de mécanisme physiopathologique patent, il est nécessaire d’interpréter les résultats épidémiologiques avec prudence et de poursuivre les recherches dans ce domaine.
Relation of Increased Chromosomal Damage to Future Adverse Cardiac Events in Patients With Known Coronary Artery Disease
2008, American Journal of Cardiology
Citation Excerpt :
Growing evidence indicates that this damage may be involved in the early-phase and/or acute complications of atherosclerosis.1–4 For instance, the loss of heterozygosity and microsatellite instability were observed in DNA extracted from human atherosclerotic plaques compared with DNA extracted from adjacent normal tissue, suggesting that the genomic destabilization of specific genes could be an important molecular mechanism associated to the atherogenic process.9–15 Moreover, the existence of chromosomal aneuploidy in endothelial cells may be important in atherogenesis by increasing low-density lipoprotein uptake to the subendothelial intima.6
Somatic deoxyribonucleic acid (DNA) damage has been associated with early-phase and/or acute complications of atherosclerosis. However, it remains unclear whether circulating levels of DNA damage have prognostic value in patients with coronary artery disease (CAD). The aim of this study was to assess the prognostic significance of chromosomal DNA damage in human lymphocytes on the rate of major adverse cardiovascular events in patients with CAD. A follow-up prospective cohort study was carried out of 178 patients (153 men, mean age 61.9 ± 9.7 years) with angiographically proved CAD who underwent micronucleus assay, a sensitive biomarker of chromosomal damage and genetic instability, from March 1999 and June 2001. During a mean follow-up period of 51.4 ± 23.8 months, 58 patients had major adverse cardiovascular events (cardiac death, myocardial infarction, stroke, congestive heart failure, unstable angina, or coronary and peripheral revascularization). The overall event-free survival rates were 77.5%, 70.4%, and 49.0% in patients in the lower, middle, and upper tertiles of micronucleus level, respectively (log rank = 11.5, p = 0.003). In a multivariate Cox regression model, only the upper tertiles were significantly associated with a higher risk for major adverse cardiovascular events (hazard ratio 2.2, 95% confidence interval 1.1 to 4.7, p = 0.03). In conclusion, levels of peripheral chromosomal DNA damage may be a new sensitive biomarker of prognostic stratification in patients with known CAD.

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¹: To whom correspondence should be addressed at Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., 116 35 Athens, Greece. Fax: 301-7226469.

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Regular ArticleLoss of Heterozygosity and Microsatellite Instability in Human Atherosclerotic Plaques

Abstract

Regular Article
Loss of Heterozygosity and Microsatellite Instability in Human Atherosclerotic Plaques