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Over Expression of Dimethylarginine Dimethylaminohydrolase‐1 (DDAH1) Slows Progression Fibrocalcific Aortic Valve Stenosis in Hypercholesterolemic Mice
Author(s) -
Zhang Bin,
Oehler Elise A.,
Roos Carolyn M.,
Arghami Arman,
Miller Jordan D.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.137.11
Subject(s) - medicine , asymmetric dimethylarginine , cardiology , aortic valve , endothelial dysfunction , aortic valve stenosis , stenosis , nitric oxide , endocrinology , chemistry , arginine , biochemistry , amino acid
Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, is primarily degraded by DDAH1. We tested the hypotheses that over expression DDAH1 reduces endothelial dysfunction and slows progression of fibrocalcific aortic valve disease (FCAVD) in hypercholesterolemic mice. We used low density lipoprotein receptor‐deficient, apolipoprotein B100‐only (LA) mice that were either wild‐type (D 0/0 ) or overexpressed human DDAH1 (D Tg/0 ). Systolic blood pressure (SBP, tail cuff), vasomotor function (isolated organ bath), and aortic valve function (echocardiography), were measured at 3 and 6 month time points. Compared to LA‐D 0/0 mice, SBP was reduced by ~15 mmHg in LA‐D Tg/0 mice at both 3 and 6 months (p < 0.05). Although aortic endothelial function progressively declined with prolonged hypercholesterolemia, there were no differences between LA‐D 0/0 and LA‐D Tg/0 mice. While aortic valve function was similar between LA‐D 0/0 and LA‐D Tg/0 mice at 3 months (peak transvalvular velocity: 1.95±0.09 m/sec versus 2.03±0.07 m/sec), overexpression of DDAH1 slowed progression of valvular dysfunction at 6 months (2.07±0.10 m/sec versus 2.30±0.05 m/sec). In conclusion, our data suggest that increasing DDAH1 may be an effective therapeutic strategy to slow progression of FCAVD, and is likely to exert protective effects independent of changes in systemic endothelial function.