title: Simvastatin prevents vascular complications in the chronic reactive oxygen species murine model of systemic sclerosis.
abstract: Aims Systemic sclerosis (SSc) is characterized by vasculopathy and organ fibrosis. Although microvascular alterations are very well characterized, structural and functional abnormalities of large vessels are not well defined. Therefore, we evaluated the effect of simvastatin administration on aortic and small renal arteries thickening, and on myofibroblasts differentiation in a murine model of SSc. Methods and results SSc was induced in BALB/c mice by daily subcutaneous injections of hypochlorous acid (HOCl, 100 μl) for 6 weeks. Mice (n = 23) were randomized to receive: HOCl (n = 10); HOCl plus simvastatin (40 mg/kg; n = 8); or vehicle (n = 5). Simvastatin administration started 30 min after HOCl injection, and up to week 6. Aortic and small renal arteries intima-media thickness was evaluated by histological analysis. Immunostaining for α-smooth muscle actin (SMA), vascular endothelial growth factor receptor 2 (VEGFR2), and CD31 in aortic tissues was performed to evaluate myofibroblast differentiation and endothelial markers.In HOCl-treated mice, intima-media thickening with reduced lumen diameter was observed in the aorta and in small renal arteries and simvastatin administration prevented this increase. Aortic and renal myofibroblasts count, as expressed by α-SMA + density, was lower in the group of mice treated with simvastatin compared to HOCl-treated mice. Simvastatin prevented the reduction in VEGFR2 and CD31 expression induced by HOCl. Conclusions The administration of simvastatin regulates collagen deposition in the aortic tissues and in the small renal arteries by modulating myofibroblasts differentiation and vascular markers. Further studies are needed to better address the effect of statins in the macrovascular component of SSc.
authors: a Department of Clinical and Experimental Medicine , University of Messina , Messina , Italy ;
authors: Alessandra
authors: A
authors: Bitto
authors: a Department of Clinical and Experimental Medicine , University of Messina , Messina , Italy ;
authors: Gian Luca
authors: GL
authors: Bagnato
authors: a Department of Clinical and Experimental Medicine , University of Messina , Messina , Italy ;
authors: Gabriele
authors: G
authors: Pizzino
authors: b Department of Medicine , University of Louisville , Louisville , KY , USA ;
authors: William Neal
authors: WN
authors: Roberts
authors: a Department of Clinical and Experimental Medicine , University of Messina , Messina , Italy ;
authors: Natasha
authors: N
authors: Irrera
authors: a Department of Clinical and Experimental Medicine , University of Messina , Messina , Italy ;
authors: Letteria
authors: L
authors: Minutoli
authors: a Department of Clinical and Experimental Medicine , University of Messina , Messina , Italy ;
authors: Giuseppina
authors: G
authors: Russo
authors: a Department of Clinical and Experimental Medicine , University of Messina , Messina , Italy ;
authors: Francesco
authors: F
authors: Squadrito
authors: a Department of Clinical and Experimental Medicine , University of Messina , Messina , Italy ;
authors: Antonino
authors: A
authors: Saitta
authors: a Department of Clinical and Experimental Medicine , University of Messina , Messina , Italy ;
authors: Gian Filippo
authors: GF
authors: Bagnato
authors: c Department of Paediatric, Gynaecological, Microbiological and Biomedical Sciences , University of Messina , Messina , Italy.
authors: Domenica
authors: D
authors: Altavilla
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D059168:Carotid Intima-Media Thickness; D002454:Cell Differentiation / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006997:Hypochlorous Acid / Q000008:administration & dosage; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019821:Simvastatin / Q000008:administration & dosage*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis
chemical_list: D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017382:Reactive Oxygen Species; D006997:Hypochlorous Acid; D003094:Collagen; D019821:Simvastatin; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Animal model; aorta; hypochlorous acid; reactive oxygen species; systemic sclerosis