| Abstract |
Over the past three decades many cellular and molecular steps of atherosclerosis development have been well recognized and understood. Atherosclerosis is a complex systemic condition where endothelium and vascular smooth muscle cells (VSMCs), macrophages, T-lymphocytes, and platelets interact with each other and produce in combination a vascular injury-like response. Chemotactic factors that affect leukocyte chemotaxis, mitogens and growth factors that cause proliferation of connective tissue, macrophages, VSMCs and endothelial cells, promote atherosclerotic lesion formation. Production and uptake of oxidized low-density lipoprotein (ox-LDL) by the endothelium and macrophages causes further injury to the vessel walls, while the formation of nitric oxide (NO) modulates vasomotor tone. The aim of this study, was initially to find out lesions at the level of microsatellite DNA located in the regions where the genes of the human mismatch repair system (MMR), are located. As a second step, we tested more microsatellite DNA markers, in order to find genes associated with atherosclerosis development. According to our first results, we found that: a) the genetic loci hMSH2, hPMS1 and hMLH1 are involved in atherosclerotic plaque formation at a 28%. b) loss of heterozygosity, LOH, or allelic imbalance,AI, is detected in atherosclerotic plaques and c) fractional regional loss, FRL, was 0,021, 0,021 and 0,026 in the forementioned genetic loci respectively. These observations seem to be the result of the focal monoclonal proliferation of genetically distinct VSMCs. To elucidate the potential importance of DNA alterations in the pathology of atherosclerosis we screened DNA from aortic atheromas for microsatellite alterations in markers previously associated with the disease. We assayed seventy eight aortic atheromas compared to correspondent venous blood DNA. Thirtythree histologically normal aortic tissues in comparison to their correspondent blood samples were also examined as a control group. LOH was found in 47,4% of atherosclerotic cases and in 18,2% of controls in at least one locus. The LOH incidence was found to be associated to atherosclerosis risk with an odds ratio value of 4,06, 95% CI 1,50 to 10,93. Comparison of the profiles of microsatellite DNA alterations between cases and controls revealed that 1p32-p31, 1q22-q25, 2q35 and 6p21.3 were significantly X affected in atherosclerotic cases (p<0,05). In these genomic regions VCAM1, SELE, APEG1 and AIF1 genes have been mapped respectively. In conclusion, as far as the first part of the study is concerned, the genetic lesions in MMR genes in atherosclerotic plaques, seem to be of not important interest. At the second part of the study, the detailed assay of multiple genetic loci of the human genome, shows that these genetic lesions form an atherosclerotic risk factor for atherosclerosis. Our data suggest that genomic rearrangements in atherosclerosis may be directly linked with disease development as an inflammatory vascular wound healing response. Genes involved in leukocyte adhesion, vascular smooth muscle cells growth, differentiation and migration, were found affected by somatic genomic alterations in atheromas and could provide the trigger to disease development. XI
|
Search
