Statins stimulate the production of a soluble form of the receptor for advanced glycation end products.
The beneficial effects of statin therapy in the reduction of cardiovascular pathogenesis, atherosclerosis, and diabetic complications are well known. The receptor for advanced glycation end products (RAGE) plays an important role in the progression of these diseases. In contrast, soluble forms of RAGE act as decoys for RAGE ligands and may prevent the development of RAGE-mediated disorders. Soluble forms of RAGE are either produced by alternative splicing [endogenous secretory RAGE (esRAGE)] or by proteolytic shedding mediated by metalloproteinases [shed RAGE (sRAGE)]. Therefore we analyzed whether statins influence the production of soluble RAGE. Lovastatin treatment of either mouse alveolar epithelial cells endogenously expressing RAGE or HEK cells overexpressing RAGE caused induction of RAGE shedding, but did not influence secretion of esRAGE from HEK cells overexpressing esRAGE. Lovastatin-induced secretion of sRAGE was also evident after restoration of the isoprenylation pathway, demonstrating a correlation of sterol biosynthesis and activation of RAGE shedding. Lovastatin-stimulated induction of RAGE shedding was completely abolished by a metalloproteinase ADAM10 inhibitor. We also demonstrate that statins stimulate RAGE shedding at low physiologically relevant concentrations. Our results show that statins, due to their cholesterol-lowering effects, increase the soluble RAGE level by inducing RAGE shedding, and by doing this, might prevent the development of RAGE-mediated pathogenesis.
['Quade-Lyssy|Patricia|P|', 'Kanarek|Anna Maria|AM|', 'Baiersdörfer|Markus|M|', 'Postina|Rolf|R|', 'Kojro|Elzbieta|E|']
D000818:Animals D019086:Bridged Bicyclo Compounds, Heterocyclic D002460:Cell Line D002784:Cholesterol D004305:Dose-Response Relationship, Drug D013186:Farnesyl-Diphosphate Farnesyltransferase D006801:Humans D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors D008148:Lovastatin D051379:Mice D000067759:Receptor for Advanced Glycation End Products D011971:Receptors, Immunologic D012995:Solubility D014233:Tricarboxylic Acids D047392:beta-Cyclodextrins
atherosclerosis diabetic complications ADAM 10 hypercholesterolemia