The Roles Lumican in the Aortic and Pulmonic Pathophysiology

Lumican, a member of the small-leucine-rich-proteoglycan (SLRP) family, is predominantly localized in the areas of pathological fibrosis including the thickened intima of human coronary arteries, ischemic and reperfused hearts. The extracellular matrix (ECM) — elastin, collagens, structural glycoproteins and proteoglycans — provides a structural framework essential for the functional properties of vessel walls. During the occurrence of vascular pathologies, such as aortic aneurysm and aortic dissection, the balance between proteases and their inhibitors is temporally destroyed through the induction of matrix metalloproteinases (MMPs) gene expression secreting by nflammatory cells. Macrophages in the media and adventitia play an important role in expansive atherosclerotic remodeling via ECM degradation and vascular smooth muscle cells (VSMC) reduction. At the same time, endogenous tissue inhibitors of metalloproteinases (TIMPs) reduce excessive proteolytic ECM degradation by MMPs. The balance between MMPs and TIMPs plays a major role in vascular remodeling. Moreover, vascular cells are very sensitive to their hemodynamic environment. In the case of pulmonary arterial hypertension (PAH) is a chronic lung disease. This process requires fibrocytes, modification of the ECM, of cell-matrix interactions, and stem cells, which mainly involves extracellular proteases. In conclusion, vascular remodeling requires modification of the ECM, VSCMs, endothelium, and of cell-matrix interactions through MMP/TIMPs. Lumican plays an important role in these processes including PAH, because we recently detected the disarray of ECM architecture of the cardiovascular system in lumican-null mice. Our hypothesis is that lumican should be an important SLRP in the vascular remodeling, and can be partially rescued by AT1 blocker.

Project ID:PC10001-1155
External Project ID:NSC99-2314-B182A-106-MY3