Chymase bound to heparin is resistant to its natural inhibitors and capable of proteolyzing high density lipoproteins in aortic intimal fluid.

Degranulated mast cells are present in the human arterial intima. After degranulation of rat serosal mast cells, the secreted neutral serine protease chymase remains bound to the heparin proteoglycan matrix of the exocytosed granules, forming granule remnants. Addition of granule remnants to human aortic intimal fluid results in proteolysis of the apoAI present in the intimal fluid, which contains physiological inhibitors of chymase. To study the physiological mechanism of this protection of granule remnant-bound chymase against its inhibitors, we performed experiments using HDL3 as substrate. Chymase, when bound to the heparin proteoglycans of granule remnants, but not when released from them, resisted inhibition by the mammalian protease inhibitors alpha1-antitrypsin, alpha2-antichymotrypsin, alpha2-macroglobulin, and eglin C. Importantly, the heparin proteoglycan-bound chymase, but not unbound chymase, degraded its inhibitor (alpha1-antitrypsin) in the presence of its substrate (HDL3). Finally, binding to heparin proteoglycans of a physiological inhibitor of chymase (mucus protease inhibitor (MPI)) or of another substrate of chymase (LDL) did not inhibit the degradation of HDL3 by granule remnant-bound chymase. This study demonstrates that binding of chymase to the heparin proteoglycan chains of the exocytosed mast cell granules allows the protease to remain active and degrade HDL3 in the presence of its physiological inhibitors and in the presence of high concentrations of LDL, such as are found in the interstitial fluid of the arterial intima.