Molecular Epidemiology of Cardiovascular Diseases and Glaucoma

Abstract

SS3-05 Introduction: Several chronic degenerative diseases share common pathogenic mechanisms such as DNA damage, oxidative stress, and chronic inflammation. Methods: Bulky DNA adducts and 8-oxo-dG were measured by 32P postlabeling in human and rat tissues. Metabolic polymorphisms were evaluated by RFLP-PCR. Results and Discussion: DNA adducts in abdominal aorta smooth muscle cells (SMCs) from 85 atherosclerotic patients were significantly correlated with atherogenic risk factors, including age, number of cigarettes, hypertension, blood triglycerides, and total/high-density lipoprotein cholesterol, fluorescent DNA adducts, and 8-oxo-dG. 8-Oxo-dG levels were 3-fold higher in the aorta inner layer than in the corresponding medium layer. Ethenodeoxyadenosine was significantly higher in SMC from current smokers than in SMC from nonsmokers or former smokers. The 4977-bp mtDNA deletion was detected in aorta SMC. Plasma malondialdehyde was correlated with the number of cigarettes. Plasma homocysteine was higher in 84 atherosclerotic patients than in 74 controls. In atherosclerotic patients, plasma homocysteine was positively correlated with blood triglycerides and inversely correlated with total glutathione and fruit consumption. Moreover, it was increased by homozygosity for slow MTHFR. DNA adducts were increased in patients having a null GSTM1 genotype, whereas GSTT1, NAT1, and NAT2 did neither affect DNA adducts nor 8-oxo-dG. Thrombophilic polymorphisms affected the 4% to 5% of the atherosclerotic patients. Formation of DNA adducts in the thoracic aorta of smoke-exposed rats was modulated by the oral administration of chemopreventive agents. DNA adducts in rodent heart accumulate with age and with exposure to cigarette smoke. The heart was quite sensitive to smoke-induced DNA alterations and was not effective in their removal. Because cardiac myocytes are perennial cells, they are not prone to develop cancer in adults, but occurrence of DNA damage is presumably associated with degenerative conditions. Interestingly, smoke-induced DNA adducts in the rat heart were increased by the simultaneous ingestion of alcohol, whereas they were attenuated by chemopreventive drugs and dietary agents. Glaucoma is the most frequent cause of irreversible blindness worldwide. We demonstrated that a significant increase of 8-oxo-dG correlated with the increase of intraocular pressure and with visual field defects occurs in trabecular meshwork cells of patients with open-angle glaucoma. Both within controls and patients with glaucoma, 8-oxo-dG levels were significantly higher in subjects having a GSTM1-null polymorphism. Conclusions: The results obtained in both humans and animal models suggest that DNA alterations occur not only in cancer but also in cardiovascular diseases and glaucoma.