Functional role for toll-like receptors in atherosclerosis and arterial remodeling.
OBJECTIVE
Activation of inflammatory cascades is causally related to the development of atherosclerotic disease. Toll-like receptors are innate immune receptors that recognize pathogen-associated molecular patterns. In this review the pathways by which toll-like receptors might play a role in the development and progression of atherosclerosis will be discussed according to recent literature.


RESULTS
Toll-like receptors are expressed in atherosclerotic tissue. Next to pathogens, endogenous toll-like receptor ligands have been linked with the development of arterial occlusive disease. In mouse models of hyperlipidemia, a potential role for the toll-like receptor pathway has been suggested in hypercholesterolemia-induced atherosclerosis. Recent in-vitro studies revealed a mechanism by which toll-like receptor ligation results in a strong inhibition of cholesterol efflux from macrophages. In addition, oxidized lipoproteins interact with toll-like receptors. Furthermore, activation of the apoptotic cascade, which is important during atherogenesis, enhances the toll-like receptor pathway resulting in upregulation of proinflammatory cytokines. Human epidemiologic studies have linked TLR4 polymorphism with atherosclerosis. However, data on the association between atherosclerosis progression and TLR4 polymorphisms are conflicting. Next to plaque growth, arterial remodeling is an important determinant of luminal narrowing in atherosclerosis. Recently, a possible role for TLR4 signaling in arterial remodeling has been revealed in mouse models.


CONCLUSIONS
A clarification of the molecule [corrected] mechanisms by which the toll-like receptor signaling cascade influences atherosclerosis might [corrected] lead to novel strategies to intervene in the development of this life-threatening disease.
Vink
Aryan
A
Department of Pathology and Experimental Cardiology Laboratory, University Medical Centre, and Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
de Kleijn
Dominique P V
DP
Pasterkamp
Gerard
G
D000818:Animals; D017209:Apoptosis; D001158:Arteries / Q000473:pathology*; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D020257:Ventricular Remodeling
D008024:Ligands; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors