Effects of Cytolknes and Monocytes on Matix Metalloproteinases in Human Vascular Smooth Muscle Cell Cultures by

In coronary arteries, smooth muscle cells (SMCs) normally regulate the metabolism of matrix molecules in atherosclerotic plaques. Excess matrix degradation may render the plaque vulnerable to rupture, possibly triggering a myocardial infarction. This research investigated how cytokines affect the secretion and activation of matrix metalloproteinases (MMPs) and the secretion of tissue inhibitors of MMPs (TIMPs) in SMC cultures modeling plaque tissue. The cytokines interleukin-1, tumor necrosis factor alpha (TNF-ax), and platelet-derived growth factor induced secretion of collagenase and stromelysin by SMCs, but in serum-free conditions, they did not increase degradation of collagen or proteoglycans. This was consistent with the observation that little of the induced MMPs were fully activated. To evaluate conditions that promote MMP activation, physiological amounts of plasminogen were added to cultures treated with TNF-oc. In SMC cultures, plasminogen was converted to plasmin, which activated MMPs. TNF-, however, induced the secretion of plasminogen activator inhibitor type 1 (PAI-1) in a concentration-dependent manner. High concentrations of TNF-a inhibited MMP activation by blocking plasmin formation. Plasminogen alone also induced secretion and activation of collagenase and stromelysin, as well as secretion of PAI-1. Even when levels of activated MMPs were greatly increased by plasminogen and TNF-a, TIMP-1 levels also increased, and matrix degradation remained unchanged. Interactions between monocytes and SMCs were also studied. Monocytes induced collagenase and stromelysin secretion by SMCs through an interleukin-l-dependent paracrine pathway. Activation of these MMPs occurred in the absence of exogenous plasminogen, but the extent of activation depended on several factors, including the phenotypes of both SMCs and monocytes. Monocytes did not consistently affect TIMP-1 in SMC cultures. When monocytes caused the secretion and activation of MMPs and simultaneously decreased TIMP-1 secretion, matrix degradation did increase, but lysosomal enzymes released by cell death may have played a role.