The structural organization and resiliency of large blood vessels is provided by the elastin-rich extracellular matrix of the media. Elastin is a covalently crosslinked polymer of tropoelastin, the secreted precursor protein, which are assembled into fibers on a microfibrillar scaffold. Unlike most proteins, elastic fiber production is limited to a brief period of development, beginning during fetal growth and peaking during early neonatal periods. Thereafter, fibrillogenesis declines rapidly. By maturity, assembly of elastic fibers is complete, and active synthesis of tropoelastin plummets. Several important vascular diseases, however, are characterized by overt changes in elastin production and integrity. For example, in hypertension and atherosclerosis, tropoelastin production is re-initiated leading to an abnormal accumulation of elastic fibers and altered hemodynamic properties. In contrast, selective degradation of elastic lamellae in abdominal aortic aneurysms (AAA) severely compromises the integrity of vessel wall. Tropoelastin expression, however, is not re-initiated in AAA, even though there is massive loss and, hence, need for repair of elastic fibers in these arteries. We hypothesize that the mechanisms that control the production of proteins needed for elastic fiber production, mechanisms that accurately re-initiate fibrillogenesis in other vascular diseases, are inoperative in AAA. Our studies have demonstrated that the cessation of tropoelastin production is controlled strictly by a post-transcriptional mechanism that mediates an accelerated decay of tropoelastin mRNA. Although the gene continues to transcribe tropoelastin pre-mRNA at the same rate in neonatal and adult tissue, marked instability of the fully-processed transcript prevents synthesis of tropoelastin protein in adult tissue. We have demonstrated that a developmentally-regulated cytosolic protein interacts specifically with a 18-nucleotide sequence within an open-reading frame element of tropoelastin mRNA and that this interaction is associated with accelerated decay of the transcript. Our data demonstrates that re-initiation of tropoelastin expression is associated with repression of this cytosolic factor. For this application, we predict that the tropoelastin mRNA-binding protein remains active, thus barring elastin production at sites of elastin breakdown in AAA tissue.
Our aims are to isolate this factor, demonstrate its role in mRNA turnover, determine the mechanism of how it mediates transcript degradation, and assess its activity in AAA and atherosclerotic tissues. This work will provide fundamental information on how production of a key vascular protein is regulated. ? ?
| Choi, Eric T; Collins, Emily T; Marine, Leopoldo A et al. (2005) Matrix metalloproteinase-9 modulation by resident arterial cells is responsible for injury-induced accelerated atherosclerotic plaque development in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 25:1020-5 |
| Choi, Eric T; Khan, M Faisal; Leidenfrost, Jeremy E et al. (2004) Beta3-integrin mediates smooth muscle cell accumulation in neointima after carotid ligation in mice. Circulation 109:1564-9 |
