Patients with a family history of atherosclerotic disease are at higher risk of developing significant atherosclerotic disease, and several genes have been associated with worse manifestations of atherosclerosis . The genes which transmit a heritable trait of susceptibility to worse forms of atherosclerosis do not follow simple Mendelian patterns, and atherosclerotic susceptibility is likely the result of multiple genes. For example, progression of atherosclerotic lesions is associated with 'remodeling' of the microenvironment of the lesion, including degradation of the extracellular matrix, by the family of matrix metalloproteinases (MMPs). Abnormal polymorphisms in the genes for MMPs-3 and -9 have been identified, in patients suffering from more severe atherosclerosis. Similarly, a large number of genes control plasma levels of lipids, such as LDL cholesterol, HDL cholesterol, triglycerides and lipoprotein (a) (reviewed by ) which, typically in conjunction with diet, can play key roles in atherogenesis. Preliminary research into genetic alterations affecting inflammatory biomolecules, such as CRP, various in-terleukins, chemokines and Toll-like receptors (reviewed by ) suggest a heritable risk in the inflammatory component of atherosclerosis, as well.
Gene therapy is being explored to correct the imbalances of gene expression at sites of disease or at one or more organ sites to effect systemic changes. For example, in carotid atherosclerosis, local gene transfer to the arterial wall may be employed to inhibit restenosis after carotid vascular interventions, or stabilize vulnerable plaques; or gene transfer may seek to produce systemic changes in li-poprotein metabolism, for example, by targeting metabolic genes in the liver.
Recent research implicates the aging of the endo-thelial layer in the progression of atherosclerosis. Endothelium is subject to injury and must be able to replace lost endothelial cells. Recent data suggests that, as people age, endothelium becomes senescent, losing its ability to regenerate after injury. This observation adds a maladaptive healing response to injury as an age-related cause of atheroma.
Young blood vessels reconstitute defects in the endothelial layer through the formation of new endothelial cells by proliferation of neighboring vascular endothelial cells, or the recruitment of endo-thelial progenitor cells (EPCs) which circulate in the bloodstream after being formed in the bone marrow. During life, endothelial cells and the marrow precursors are called upon to divide, creating new (duplicate) cells. With each cell division, the length of chromosomal telomeres becomes shorter, called telo-meric attrition. Telomeres are repetitive nucleotide sequences found at the end of chromosomes, crucial for DNA replication and stability. The more often an endothelial cell divides, the more its chromosomal telomeres shorten. Radioautographic studies show a higher rate of turnover of endothelial cells overlying atherosclerotic lesions than cells in normal endothelium. Once telomere length shortens to a critical threshold, endothelial cells will no longer divide, a state known as senescence. Senescent endothelial cells have been found covering plaques, in autopsy studies of adults .
Endothelial senescence likely plays an important role in progression of disease but is unnecessary for the initiation of atheroma since fatty streaks can be found in the aortae and carotid arteries of healthy infants , before telomere attrition would reasonably occur. However, injury to the endothelium acceler ates endothelial senescence and, therefore, may contribute to the development of carotid atherosclerosis in younger patients exposed, for example, to carotid balloon injury or neck irradiation. Progression of atherosclerosis, in the aged, is also associated with changes in sex hormones, in both men and women.
The prevalence and extent of atheromata is increased by cigarette-smoking , hypertension, diabetes, and specific genetic diseases . In carotid atherosclerosis, cigarette-smoking has been shown to increase intralesional macrophage content, with an associated increase in intralesional inflammatory enzymes (i.e., macrophage-derived metalloelastase) which degrade vascular tissue.
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