oa Environmental Mutagenesis In Cardiovascular and Eye Diseases

To check the pathogenic role of exposure to mutagens in cardiovascular and eye disease we examined molecular damages in affected subjects. 107 atherosclerotic patients were tested for molecular alterations in aorta specimens and molecular biomarkers evaluated for their prognostic value in a 15-year follow up. Mitochondrial damage (mitochondrial DNA common deletion 4977 bp) and oxidative DNA damage (8-oxo-dG), detected at very high level in atherosclerotic aorta, were significantly related with patients survival. Physical activity dramatically decreased these biomarkers, improving survival, although with a remarkable inter-individual variability. Indeed, preventive effects of physical activity were mainly detected in patients bearing double GSTM/T homozygous deletion, which have a 3.6-year survival only in case of being sedentary while a 9.7-year survival in case of being physically active (a 30-minute walk a day). Dealing with ocular diseases, we analyzed 73 patients affected by glaucoma, the most common cause of irreversible blindness worldwide, as compared to 158 unaffected controls for the occurrence of molecular damage in the ocular trabecular meshwork, the tissue regulating aqueous humor outflow. Oxidative nuclear DNA (8-oxo-dG) and mitochondrial DNA damage (mitochondrial DNA common deletion 4977 bp) were consistently detected and tightly related with clinical variables, including intraocular pressure increase and visual field defects. Mitochondrial damage in trabecular meshwork results in apoptosis activation and cell loss, as demonstrated by proteome analysis of aqueous humor. On a comparative basis with iris and cornea, trabecular meshwork resulted to be the most sensitive tissue of the ocular anterior chamber to oxidative damage when ocular tissues collected from corneal donors were challenged with hydrogen peroxide. In the same experimental system we demonstrated that beta blockers and carbonic anhydrase inhibitor drugs, commonly used in glaucoma therapy, are able to attenuate DNA and mitochondrial damage as induced by reactive oxygen species in trabecular meshwork. These studies provide experimental evidence that molecular damage as induced by exogenous and endogenous mutagens play a pathogenic role in cardiovascular and ocular diseases by inducing nuclear and mitochondrial DNA damage.