Atherosclerosis is a chronic inflammatory disease characterized by lipid accumulation, the persistent presence of macrophages and dysregulated smooth muscle proliferation. Expression of proteinases by macrophages contributes to atherosclerotic plaque rupture and its clinical sequelae - thrombosis and infarction. Our primary research aim is to elucidate the mechanisms by which macrophage orchestrate tissue remodeling at sites of injury and inflammation.

Macrophages utilize serine proteinases, metalloproteinases and cysteine proteinases to degrade the extracellular matrix. Principal among these proteinases is the serine proteinase urokinase type plasminogen activator (uPA). uPA cleaves Arg₅₆₀-Val₅₆₁ bond of plasminogen (Plg), thereby generating plasmin, a serine proteinase with wide substrate specificity. Plasmin binds to and degrades several components of the extracellular matrix. Moreover, plasmin activates a family of matrix metalloproteinases (MMP), which degrade collagens and other matrix components. The activation of this proteinase cascade has been demonstrated to be a pivotal regulatory step for a diverse group of cellular activities including fibrinolysis, migration, matrix degradation and the release and/or activation of growth factors and cytokines.

The control of expression of macrophage proteinases and receptors, as well as, the fate of ligands bound to them are the focus of ongoing experiments.

The aims of current studies are to: (1) Determine the mechanisms by which the extracellular matrix induces a degradative phenotype in macrophages; (2) Determine whether the expression of uPA and MMPs by macrophages act in a cooperative manner to degrade extracellular matrix and release matrix-bound growth factors; (3) Determine whether the ability of TGF-b to induce a degradative phenotype in monocytes/ macrophages is regulated by differentiation-dependent and cytokine-induced alterations in TGF-b receptor expression; and (4) Determine the role of plasminogen receptors and pericellular plasmin activity in the generation of angiostatins.

Email: dfalcone@med.cornell.edu