title: Losartan decreases cardiac muscle fibrosis and improves cardiac function in dystrophin-deficient mdx mice.
abstract: Recent studies showed that chronic administration of losartan, an angiotensin II type I receptor antagonist, improved skeletal muscle function in dystrophin-deficient mdx mice. In this study, C57BL/10ScSn-Dmd(mdx)/J female mice were either untreated or treated with losartan (n = 15) in the drinking water at a dose of 600 mg/L over a 6-month period. Cardiac function was assessed via in vivo high frequency echocardiography and skeletal muscle function was assessed using grip strength testing, Digiscan monitoring, Rotarod timing, and in vitro force testing. Fibrosis was assessed using picrosirius red staining and Image J analysis. Gene expression was evaluated using real-time polymerized chain reaction (RT-PCR). Percentage shortening fraction was significantly decreased in untreated (26.9% ± 3.5%) mice compared to losartan-treated (32.2% ± 4.2%; P < .01) mice. Systolic blood pressure was significantly reduced in losartan-treated mice (56 ± 6 vs 69 ± 7 mm Hg; P < .0005). Percentage cardiac fibrosis was significantly reduced in losartan-treated hearts (P < .05) along with diaphragm (P < .01), extensor digitorum longus (P < .05), and gastrocnemius (P < .05) muscles compared to untreated mdx mice. There were no significant differences in skeletal muscle function between treated and untreated groups. Chronic treatment with losartan decreases cardiac and skeletal muscle fibrosis and improves cardiac systolic function in dystrophin-deficient mdx mice.
authors.affiliation: Division of Cardiology, Children's National Medical Center, Washington, DC, USA.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Spurney
authors.forename: Arpana
authors.initials: A
authors.lastname: Sali
authors.forename: Alfredo D
authors.initials: AD
authors.lastname: Guerron
authors.forename: Micaela
authors.initials: M
authors.lastname: Iantorno
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: Sree
authors.initials: S
authors.lastname: Rayavarapu
authors.forename: Jack
authors.initials: J
authors.lastname: van der Meulen
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D009202:Cardiomyopathies / Q000188:drug therapy / Q000209:etiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D016189:Dystrophin / Q000235:genetics; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D019808:Losartan / Q000627:therapeutic use*; D051379:Mice; D018101:Mice, Inbred mdx; D018908:Muscle Weakness / Q000188:drug therapy / Q000209:etiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D015815:Cell Adhesion Molecules; D016189:Dystrophin; C082838:Postn protein, mouse; D012333:RNA, Messenger; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D019808:Losartan