Vascular function during prolonged progression and regression of atherosclerosis in mice.

Objective: Endothelial dysfunction is associated with atherosclerosis in mice, but it is difficult to reduce cholesterol levels enough to study regression of atherosclerosis in genetically modified mice. The goal of this study was to examine vascular structure and function before and after reducing elevated plasma lipid levels with a genetic switch in Reversa mice, and identify novel mechanisms contributing to structural and functional improvements in the vasculature after reduction of blood lipids.

Methods And Results: After 6 months of hypercholesterolemia, endothelial function (maximum relaxation to acetylcholine) in aorta was impaired and responses to nitric oxide were unaffected.

Evidence for active regulation of pro-osteogenic signaling in advanced aortic valve disease.

Objective: To test the hypothesis that valvular calcium deposition, pro-osteogenic signaling, and function can be altered in mice with advanced aortic valve disease.

Methods And Results: "Reversa" mice were given a Western-type diet for 12 months and screened for the presence of aortic valve stenosis. Mice with advanced valve disease were assigned to 1 of 2 groups: (1) those with continued progression for 2 months and (2) those with regression for 2 months, in which lipid lowering was accomplished by a genetic switch.

Lowering plasma cholesterol levels halts progression of aortic valve disease in mice.

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(100/100)/Mttp(fl/fl)/Mx1-Cre+/+) reduces oxidative stress, reduces pro-osteogenic signaling, and retards the progression of aortic valve disease.