Inhibition of Mast Cell–Dependent Conversion of Cultured Macrophages Into Foam Cells With Antiallergic Drugs

Abstract

Abstract-Degranulation of isolated, rat peritoneal mast cells in the presence of low density lipoprotein (LDL) induces cholesteryl ester accumulation in cocultured macrophages with ensuing foam cell formation. This event occurs when the macrophages phagocytose LDL particles that have been bound to the heparin proteoglycans of exocytosed granules. In an attempt to inhibit such foam cell formation pharmacologically, rat peritoneal mast cells that had been passively sensitized with anti-ovalbumin-IgE were treated with 2 mast cell-stabilizing antianaphylactic drugs, MY-1250 or disodium cromoglycate (DSCG). Both drugs were found to inhibit antigen (ovalbumin)-triggered release of histamine from the mast cells, revealing mast cell stabilization. In cocultures of rat peritoneal macrophages and passively sensitized mast cells, addition of MY-1250 before addition of the antigen resulted in parallel reductions in histamine release from mast cells, uptake of [ 14 C]sucrose-LDL, and accumulation of LDL-derived cholesteryl esters in the cocultured macrophages. Similarly, when passively sensitized mast cells were stimulated with antigen in the presence of DSCG and the preconditioned media containing all substances released from the drug-treated mast cells were collected and added to macrophages cultured in LDL-containing medium, uptake and esterification of LDL cholesterol by the macrophages were inhibited. The inhibitory effects of both drugs were mast cell-specific because neither drug inhibited the ability of macrophages to take up and esterify LDL cholesterol. Analysis of heparin proteoglycan contents of the incubation media revealed that both drugs had inhibited mast cells from expelling their granule remnants. Thus, both MY-1250 and DSCG prevent mast cells from releasing the heparin proteoglycan-containing vehicles that bind LDL and carry it into macrophages. This study suggests that antiallergic pharmacological agents could be used in animal models to prevent mast cell-dependent formation of foam cells in vivo.

Mast cells and metabolic syndrome

“…When mast cells were activated by intraperitoneal administration of C48/80, a laboratory-use mast cell activator, LDL uptake by macrophages rose by 7~24-fold [94]. Like 48/80-triggered mast cell stimulation, lgE-dependent stimulation of sensitized mast cells also leads to increased uptake of LDL by cocultured macrophages, and thereby foam cell formation [95, 96]. In contrast, the mast cell stabilizer cromolyn effectively blocked mast cell–dependent LDL uptake by macrophages [95].…”

“…Like 48/80-triggered mast cell stimulation, lgE-dependent stimulation of sensitized mast cells also leads to increased uptake of LDL by cocultured macrophages, and thereby foam cell formation [95, 96]. In contrast, the mast cell stabilizer cromolyn effectively blocked mast cell–dependent LDL uptake by macrophages [95]. Along with LDL particles, high-density lipoprotein (HDL) particles constantly pass from the bloodstream into the arterial intima [91].…”

The impact of mast cells on cardiovascular diseases

“…Among the evidence collected so far it has been demonstrated that mast cells stabilized in vitro, using anti-allergic drugs, were able to, inhibit foam cell formation suggesting a direct role in plaque development (Ma and Kovanen, 2000). In accordance, several lines of in vivo research have demonstrated that aortic lipid accumulation in atherosclerosis-prone mice is reduced, when the mice have been genetically engineered to be mast cell-deficient, or when mast cell activation in mast cell-sufficient mice has been pharmacologically inhibited.…”

Mast Cell Chymase and Tryptase as Targets for Cardiovascular and Metabolic Diseases

“…Pharmacological stabilization of mast cells with their inhibitor, cromolyn (disodium cromoglycate, DSCG), reduced mast cell activation-induced atherosclerotic plaque intraplaque hemorrhage, macrophage apoptosis, vascular leakage, and CXCR2/VLA-4 (Very Late Antigen-4)-mediated recruitment of leukocytes in apolipoprotein E-deficient ( Apoe −/− ) mice [55]. Mast cell stabilizers MY-1250 and cromolyn also can prevent mast cell-mediated macrophage foam cell formation in vitro [56]. We showed that mast cell stabilization with cromolyn reduced elastase perfusion-induced AAA [54], which suggests that mast cell-derived cytokines, growth factors, proteoglycans, chymases and tryptases, or other proteases — such as cysteinyl cathepsins and MMPs — participate directly and indirectly in the pathogenesis of atherosclerosis and AAA.…”