title: Combined effects of HMG-CoA-reductase inhibition and renin-angiotensin system blockade on experimental atherosclerosis.
abstract: Therapeutic strategies to prevent atherosclerotic plaque progression and achieve plaque stabilization involve 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-reductase inhibitors (statins) and renin-angiotensin system (RAS)-blockade, but studies investigating the potentially additive effects of a combined treatment strategy are rare. We hypothesised that the adjunction of atorvastatin with telmisartan or ramipril might achieve additional effects on experimental atherosclerosis though statin-induced lipid-lowering is lacking. ApoE-/- mice were fed a high-fat diet for 12 weeks and randomized to either placebo (CON), atorvastatin (ATO), ramipril (RAM), telmisartan (TEL) or RAM+ATO and TEL+ATO (N=23 per group). RAS-blockade, but not ATO, reduced systolic blood pressure. None of the treatment regimens lowered systemic cholesterol levels or lipoprotein fractions. RAM, TEL and the combined therapy, but not ATO, significantly reduced aortic lipid deposition. All substances significantly reduced monocyte chemoattracting protein (MCP)-1 concentrations, macrophages and matrixmetalloproteinase (MMP)-9 content and enhanced plaque's content of tissue inhibitor of MMP (TIMP)-1, collagen and fibrous cap thickness, resulting in an overall decrease of advanced plaques (classified as types IV-VI). Additive effects of the adjunction were observed on MMP-9 gelatinolytic activity, interleukin (IL)-6 and IL-10 plasma levels. These results indicate that a combined treatment with RAS-blockade and statins may have additive effects on systemic cardiovascular risk markers even in the absence of lipid-reduction, although additional effects on atherosclerotic plaque progression and stability were not observed in this model.
authors.affiliation: Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Carl Neuberg Strasse 1, 30625 Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Grothusen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Bley
authors.forename: Tina
authors.initials: T
authors.lastname: Selle
authors.forename: Maren
authors.initials: M
authors.lastname: Luchtefeld
authors.forename: Karsten
authors.initials: K
authors.lastname: Grote
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schieffer
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000069059:Atorvastatin; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000097:blood; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008264:Macrophages / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D017257:Ramipril / Q000494:pharmacology; D012084:Renin-Angiotensin System / Q000187:drug effects; D000077333:Telmisartan
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; D001562:Benzimidazoles; D001565:Benzoates; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015850:Interleukin-6; D011758:Pyrroles; D016753:Interleukin-10; D000069059:Atorvastatin; D020780:Matrix Metalloproteinase 9; D017257:Ramipril; D000077333:Telmisartan