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

ObjectiveWe 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.MethodsSystemic 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.ResultsLysates of isolated mouse peritoneal mast cells containing active chymase partially proteolyzed apoA-I in α- and preβ-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.ConclusionThe 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.