TY - JOUR
T1 - Lowering plasma cholesterol levels halts progression of aortic valve disease in mice
AU - Miller, Jordan D.
AU - Weiss, Robert M.
AU - Serrano, Kristine M.
AU - Brooks, Robert M.
AU - Berry, Christopher J.
AU - Zimmerman, Kathy
AU - Young, Stephen G.
AU - Heistad, Donald D.
PY - 2009/5/26
Y1 - 2009/5/26
N2 - BACKGROUND-: Treatment of hyperlipidemia produces functional and structural improvements in atherosclerotic vessels. However, the effects of treating hyperlipidemia on the structure and function of the aortic valve have been controversial, and any effects could be confounded by pleiotropic effects of hypolipidemic treatment. The goal of this study was to determine whether reducing elevated plasma lipid levels with a "genetic switch" in Reversa mice (Ldlr-/-/Apob/Mttp/Mx1-Cre) reduces oxidative stress, reduces pro-osteogenic signaling, and retards the progression of aortic valve disease. METHODS AND RESULTS-: After 6 months of hypercholesterolemia, Reversa mice exhibited increases in superoxide, lipid deposition, myofibroblast activation, calcium deposition, and pro-osteogenic protein expression in the aortic valve. Maximum aortic valve cusp separation, as judged by echocardiography, was not altered. During an additional 6 months of hypercholesterolemia, superoxide levels, valvular lipid deposition, and myofibroblast activation remained elevated. Furthermore, calcium deposition and pro-osteogenic gene expression became more pronounced, and the aortic cusp separation decreased from 0.85±0.04 to 0.70±0.04 mm (mean±SE; P<0.05). Rapid normalization of cholesterol levels at 6 months of age (by inducing expression of Cre recombinase) normalized aortic valve superoxide levels, decreased myofibroblast activation, reduced valvular calcium burden, suppressed pro-osteogenic signaling cascades, and prevented reductions in aortic valve cusp separation. CONCLUSIONS-: Collectively, these data indicate that reducing plasma lipid levels by genetic inactivation of the mttp gene in hypercholesterolemic mice with early aortic valve disease normalizes oxidative stress, reduces pro-osteogenic signaling, and halts the progression of aortic valve stenosis.
AB - BACKGROUND-: Treatment of hyperlipidemia produces functional and structural improvements in atherosclerotic vessels. However, the effects of treating hyperlipidemia on the structure and function of the aortic valve have been controversial, and any effects could be confounded by pleiotropic effects of hypolipidemic treatment. The goal of this study was to determine whether reducing elevated plasma lipid levels with a "genetic switch" in Reversa mice (Ldlr-/-/Apob/Mttp/Mx1-Cre) reduces oxidative stress, reduces pro-osteogenic signaling, and retards the progression of aortic valve disease. METHODS AND RESULTS-: After 6 months of hypercholesterolemia, Reversa mice exhibited increases in superoxide, lipid deposition, myofibroblast activation, calcium deposition, and pro-osteogenic protein expression in the aortic valve. Maximum aortic valve cusp separation, as judged by echocardiography, was not altered. During an additional 6 months of hypercholesterolemia, superoxide levels, valvular lipid deposition, and myofibroblast activation remained elevated. Furthermore, calcium deposition and pro-osteogenic gene expression became more pronounced, and the aortic cusp separation decreased from 0.85±0.04 to 0.70±0.04 mm (mean±SE; P<0.05). Rapid normalization of cholesterol levels at 6 months of age (by inducing expression of Cre recombinase) normalized aortic valve superoxide levels, decreased myofibroblast activation, reduced valvular calcium burden, suppressed pro-osteogenic signaling cascades, and prevented reductions in aortic valve cusp separation. CONCLUSIONS-: Collectively, these data indicate that reducing plasma lipid levels by genetic inactivation of the mttp gene in hypercholesterolemic mice with early aortic valve disease normalizes oxidative stress, reduces pro-osteogenic signaling, and halts the progression of aortic valve stenosis.
KW - Aortic valve stenosis
KW - Calcification
KW - Free radicals
KW - Hypercholesterolemia
KW - Valves
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U2 - 10.1161/CIRCULATIONAHA.108.834614
DO - 10.1161/CIRCULATIONAHA.108.834614
M3 - Article
C2 - 19433756
AN - SCOPUS:67249120424
SN - 0009-7322
VL - 119
SP - 2693
EP - 2701
JO - Circulation
JF - Circulation
IS - 20
ER -