A major culprit in atheroma development is an accelerated cholesterol-laden macrophage (foam cell) formation. High density lipoproteins (HDL) are the most efficient physiological acceptors of cellular cholesterol. By promoting cellular cholesterol release (efflux), HDL particles initiate the reverse cholesterol transport (RCT) pathway from macrophage foam cells located in the arterial intima to liver for biliary excretion. We study how proteolysis of various HDL subpopulations can disrupt this anti-atherogenic function of HDL.

Mast cells are a potent source of serine proteases in the human intima. We have demonstrated that the mast cell-derived chymase is able to proteolytically modify HDL particles in vitro leading to the loss in their function as macrophage cholesterol acceptors. The small lipid-poor preβ-migrating HDL subpopulation is the most susceptible to proteolysis. Since preβ-HDL efficiently stimulate cholesterol efflux via the ABCA1 receptor pathway, proteolytic depletion of preβ impaired HDL functionality. Recently we found that acute systemic stimulation of mast cells in the mouse (anaphylactic shock) reduced the abilities of serum and peritoneal fluid to promote cholesterol efflux from cultured macrophage foam cells. At present, by applying a macrophage-specific RCT assay, we have expanded our in vivo models to evaluate the impact of HDL proteolysis on the entire RCT pathway. Our experimental in vivo systems include genetically-modified mice such as the mast-cell deficient W-sash c-kit mutant mice, and pathophysiological models that may affect RCT such as the physical restraint stress in mice.

Selected publications

Mast cell activation in vivo impairs the macrophage reverse cholesterol transport pathway in the mouse. Lee-Rueckert M, Silvennoinen R, Rotllan N, Judström I, Blanco-Vaca F, Metso J, Jauhiainen M, Kovanen PT, Escola-Gil JC. Arterioscler Thromb Vasc Biol. 2011;31:520-7.

Acidic extracellular environments strongly impair ABCA1-mediated cholesterol efflux from human macrophage foam cells. Lee-Rueckert M, Lappalainen J, Leinonen H, Pihlajamaa T, Jauhiainen M, Kovanen PT. Arterioscler Thromb Vasc Biol. 2010;30:1766-72.

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. Judström I, Jukkola H, Metso J, Jauhiainen M, Kovanen PT, Lee-Rueckert M. Atherosclerosis. 2010;208:148-54.

Association of cholesteryl ester transfer protein with HDL particles reduces its proteolytic inactivation by mast cell chymase. Lee-Rueckert M, Vikstedt R, Metso J, Jauhiainen M, Kovanen PT. J Lipid Res. 2008;49:358-68.

Mast cell proteases: physiological tools to study functional significance of high density lipoproteins in the initiation of reverse cholesterol transport. Lee-Rueckert M, Kovanen PT. Atherosclerosis. 2006;189:8-18 (Review).

Juan Carlos Escola-Gil, PhD,

Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Mast cells, better known as allergy cells, are proinflammatory effector cells present in the human arterial intima and in evolving atherosclerotic lesions. Our understanding of the relationship between the proatherogenic activities of arterial mast cells (MCs) and the development of atherosclerotic lesions is advancing. Experiments in vitro, in vivo experiments in animals, and immunohistologic studies of human coronary samples have uncovered mechanisms by which activated mast cells could participate in the development of the lesions. When activated, mast cells acutely expel a fraction of their cytoplasmic granules, which are filled with a wide selection of heparin-bound preformed mediators. The microenvironmental targets of these effector molecules are various lipoprotein particles in the intimal fluid, components of the extracellular matrix, and intimal cells neighboring the activated mast cells. We propose that by promoting cholesterol accumulation and plaque vulnerability and by locally regulating hemostasis, MCs in atherosclerotic lesions have the potential to contribute to the clinical outcomes of atherosclerosis, such as myocardial infarction and stroke.

Selected publications

Lee-Rueckert M, Silvennoinen R, Rotllan N, Judström I, Blanco-Vaca F, Metso J, Jauhiainen M, Kovanen PT, Escola-Gil JC. Mast cell activation in vivo impairs the macrophage reverse cholesterol transport pathway in the mouse. Arterioscler Thromb Vasc Biol. 2011;31:520-7.

Swedenborg J, Mäyränpää MI, Kovanen PT. Mast cells: important players in the orchestrated pathogenesis of abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol. 2011;31:734-40.

Lappalainen J, Lindstedt KA, Oksjoki R, Kovanen PT. OxLDL-IgG immune complexes induce expression and secretion of proatherogenic cytokines by cultured human mast cells. Atherosclerosis. 2011;214:357-63

Heikkilä HM, Trosien J, Metso J, Jauhiainen M, Pentikäinen MO, Kovanen PT, Lindstedt KA. Mast cells promote atherosclerosis by inducing both an atherogenic lipid profile and vascular inflammation. J Cell Biochem. 2010;109:615-23.

Strbian D, Kovanen PT, Karjalainen-Lindsberg ML, Tatlisumak T, Lindsberg PJ. An emerging role of mast cells in cerebral ischemia and hemorrhage. Ann Med. 2009;41:438-50.

Kovanen PT. Mast cells in atherogenesis: actions and reactions. Curr Atheroscler Rep. 2009;11:214-9.