Mast cell-dependent proteolytic modification of HDL particles during anaphylactic shock in the mouse reduces their ability to induce cholesterol efflux from macrophage foam cells ex vivo.

OBJECTIVE: We have found previously that proteolytic modification of HDL by mast cell chymase in vitro reduces cholesterol efflux from cultured macrophage foam cells. Here, we evaluated whether mast cell-dependent proteolysis of HDL particles may occur in vivo, and whether such modification would impair their function in inducing cellular cholesterol efflux ex vivo.

METHODS: Systemic activation of mast cells in the mouse was achieved by intraperitoneal injection of a high dose of the mast cell-specific noncytotoxic degranulating agent, compound 48/80. Serum and intraperitoneal fluid were then evaluated for degradation of HDL apolipoproteins and for their potential to act as cholesterol acceptors from cultured mouse macrophage foam cells.

RESULTS: Lysates of isolated mouse peritoneal mast cells containing active chymase partially proteolyzed apoA-I in alpha- and prebeta-HDL particles in mouse serum in vitro, and, when injected into the mouse peritoneal cavity, the lysates also degraded endogenous apoA-I in peritoneal fluid in vivo. Systemic activation of mast cells in mast cell-competent mice, but not in mast cell-deficient (W-sash c-kit mutant) mice, reduced the ability of serum and intraperitoneal fluid derived from these animals to promote efflux of cellular cholesterol. This inhibitory effect was related to mast cell-dependent proteolytic degradation of apoA-I, apoA-IV, and apoE, i.e., the HDL-associated apolipoproteins that are efficient inducers of cholesterol efflux.

CONCLUSION: The present results document a role for extracellular mast cell-dependent proteolysis in the generation of dysfunctional HDL, and suggest an inhibitory role for mast cells in the initial step of reverse cholesterol transport in vivo.