alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, and alpha 2-macroglolbulin are the antiapoptotic factors of vascular smooth muscle cells

Serum depletion induces cell death. Whereas serum contains growth factors a nd adhesion molecules that are important for survival, serum is also likely to have antiapoptotic factor(s). We show here that the plasma proteinase i nhibitors alpha1-proteinase inhibitor, alpha1-anti-chymotrypsin, and alpha2 -macroglobulin function as critical antiapoptotic factors for human vascula r smooth muscle cells. Cell survival was assured when serum-free medium was supplemented with any one or all of the above serine proteinase inhibitors . In contrast, the cells were sensitive to apoptosis when cultured in mediu m containing serum from which the proteinase inhibitors were removed. The a ntiapoptotic effect conferred by the proteinase inhibitors was proportional to proteinase inhibitory activity. Without proteinase inhibitors, the extr acellular matrix was degraded, and cells could not attach to the matrix. ce ll survival was dependent on the intact extracellular matrix. In the presen ce of the caspase inhibitor z-VAD, the cells detached but did not die. The activity of caspases was elevated without proteinase inhibitors; in contras t, caspases were not activated when medium was supplemented with one of the proteinase inhibitors. In conclusion, the plasma proteinase inhibitors pre vent degradation of extracellular matrix by proteinases derived from cells. Presumably an intact cell-matrix interaction inhibits caspase activation a nd supports cell survival.