title: Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice.
abstract: Angiotensin (Ang) II contributes to the development of atherosclerosis, while Ang-(1-7) has atheroprotective actions. Accordingly, angiotensin-converting enzyme 2 (ACE2), which breaks-down Ang II and forms Ang-(1-7), has been suggested as a target against atherosclerosis. Here we investigated the actions of diminazene, a recently developed ACE2 activator compound, in a model of vulnerable atherosclerotic plaque. Atherosclerotic plaque formation was induced in the carotid artery of ApoE-deficient mice by a shear stress (SS) modifier device. The animals were treated with diminazene (15mg/kg/day) or vehicle. ACE2 was strongly expressed in the aortic root and low SS-induced carotid plaques, but poorly expressed in the oscillatory SS-induced carotid plaques. Diminazene treatment did not change the lesion size, but ameliorated the composition of aortic root and low SS-induced carotid plaques by increasing collagen content and decreasing both MMP-9 expression and macrophage infiltration. Interestingly, these beneficial effects were not observed in the oscillatory SS-induced plaque. Additionally, diminazene treatment decreased intraplaque ICAM-1 and VCAM-1 expression, circulating cytokine and chemokine levels and serum triglycerides. In summary, ACE2 was distinctively expressed in atherosclerotic plaques, which depends on the local pattern of shear stress. Moreover, diminazene treatment enhances the stability of atherosclerotic plaques.
authors: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland. Electronic address: rodrigo.fragasilva@epfl.ch.
authors: Rodrigo A
authors: RA
authors: Fraga-Silva
authors: Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy.
authors: Fabrizio
authors: F
authors: Montecucco
authors: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors: Fabiana P
authors: FP
authors: Costa-Fraga
authors: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy.
authors: Alessio
authors: A
authors: Nencioni
authors: First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, Genoa, Italy.
authors: Irene
authors: I
authors: Caffa
authors: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors: Maiia E
authors: ME
authors: Bragina
authors: Division of Cardiology, Faculty of Medicine, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland.
authors: François
authors: F
authors: Mach
authors: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, United States.
authors: Mohan K
authors: MK
authors: Raizada
authors: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Robson A S
authors: RAS
authors: Santos
authors: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, Brazil.
authors: Rafaela F
authors: RF
authors: da Silva
authors: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors: Nikolaos
authors: N
authors: Stergiopulos
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004133:Diminazene / Q000494:pharmacology*; D004195:Disease Models, Animal; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000188:drug therapy / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D004133:Diminazene
keywords: Angiotensin; Angiotensin-converting enzyme 2; Atherosclerosis; Diminazene; Inflammation; Plaque stability; Plaque vulnerable