Role of Retroelements in Environmental Atherogenesis

DESCRIPTION (provided by applicant): Atherosclerosis, the leading cause of morbidity and mortality in industrialized nations, is a fibro-proliferative disease associated with endothelial injury, recruitment of inflammatory cells (macrophages and T cells), expansion of vascular smooth muscle cells (vSMCs) and buildup of cholesterol and extracellular matrix within the inner lining of arteries. Clinical disease results from occlusion of vessels that feed the heart, brain, or extremities. The early stages of atherosclerosis (atherogenesis) involve inflammatory injury to the vessel wall, infiltration of macrophages and uncontrolled proliferation of vSMCs. Oxidative injury to the vessel wall is a common denominator of the atherogenic response, with elevated levels of blood cholesterol, high blood pressure, diabetes, and smoking recognized as primary risk factors. Chronic exposures to air particulates and chemicals associated with particulate matter, such as polycyclic aromatic hydrocarbons, have been associated with development or exacerbation of atherosclerosis in rodents and primates. Of relevance are the biological effects of benzo(a)pyrene (BaP), a carcinogen present in various forms of pollution and metabolized by cytochromes P450 to intermediates that damage DNA and cause oxidative stress. Repeated exposure of vSMCs to BaP in vivo or in vitro induces atherosclerotic changes within the vascular wall. The molecular mechanisms responsible for BaP atherogenesis involve transcriptional deregulation of gene expression and DNA damage. Of interest are responses involving activation of the c-Ha-ras gene and long interspersed nuclear elements (LINE 1 or L1) in human and murine vSMCs. L1s have emerged as interesting genomic targets in environmental atherogenesis since members of this family modify genetic programs in somatic cells through a "copy and paste" mechanism involving RNA intermediates, reverse transcriptase and endonuclease. To continue previous investigations, studies are proposed in this application to evaluate the expression of L1 during the course of atherosclerotic disease progression in the Apoetm1Unc mouse model, to evaluate the impact of vascular specific expression of L1 on atherosclerotic lesion occurrence and severity, and to elucidate molecular mechanisms of L1 activation in vSMCs and macrophages, two of the principal cell types in atherosclerosis. The central hypothesis to be tested is that progression of plaque formation is associated with L1 overexpression and genomic instability in cells within the atherosclerotic plaque. Further, it is hypothesized that L1 activation is mediated via epigenetic mechanisms that increase promoter activity and RNA polymerase II efficiency. These studies are the first to systematically examine the role of L1 and retrotransposition in diseases of the vascular wall. PUBLIC HEALTH RELEVANCE: Atherosclerosis continues to be responsible for most cases of cardiovascular mortality in the US. Recent studies have shown that the incidence of this disease is accelerated by environmental contaminants, but the genetic mechanisms that mediate this relationship are not fully understood. Studies are proposed in this application to study the role of virus-like sequences in the onset and progression of environmentally-induced atherosclerosis in experimental systems.