Diseases such as atherosclerosis, diabetes, hyperlipidemia and hypertension are associated with vascular function and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Although many factors influence these cellular changes, angiotensin II (Ang II) appears to be one of the most important. In pathological conditions, through its vasoconstrictor, mitogenic, proinflammatory and profibrotic actions, Ang II contributes to altered vascular tone, endothelial dysfunction, structural remodeling and vascular inflammation. Many of the known functions of Ang II are mediated via a high affinity G protein-coupled receptor, now designated AT1R. We hypothesize that aberrant regulation of AT1R levels may play a pivotal role in cardiovascular disease. A number of recent studies suggest that AT1R expression levels are predominantly regulated by post-transcriptional mechanisms. The current proposal represents the first in-depth study to investigate the post-transcriptional mechanisms that regulate the human AT1R gene.
The Specific Aims of the Proposal are to: (1) Investigate the molecular mechanisms that regulate the selection of hAT1R mRNA 3'-UTR polyadenylation sites;(2) Test the hypothesis that the 3'- UTR regulates hAT1R mRNA stability;(3) Test the hypothesis that the 3'-UTR regulates the translational efficiency of hAT1R mRNAs;(4) Test the hypothesis that hAT1 R expression can be regulated by the binding of microRNAs to the 3'-UTR of hAT1R mRNAs;(5) Test the hypothesis that the hAT1R 3'-UTR polymorphism (A1166C) reduces the ability of miRNA-155 and/or miRNA-365 to inhibit hAT1R expression. We hypothesize that dysregulation of these processes may lead to the overproduction of hATIRs and may initiate a cascade of pathological events and eventually lead to cardiovascular disease. The knowledge gained from the proposed study may lead to the development of novel therapeutics for disease states in which aberrant regulation of hAT1 R expression occurs.
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