title: Circulating Markers Reflect Both Anti- and Pro-Atherogenic Drug Effects in ApoE-Deficient Mice.
abstract: BACKGROUND: Current drug therapy of atherosclerosis is focused on treatment of major risk factors, e.g. hypercholesterolemia while in the future direct disease modification might provide additional benefits. However, development of medicines targeting vascular wall disease is complicated by the lack of reliable biomarkers. In this study, we took a novel approach to identify circulating biomarkers indicative of drug efficacy by reducing the complexity of the in vivo system to the level where neither disease progression nor drug treatment was associated with the changes in plasma cholesterol. RESULTS: ApoE-/- mice were treated with an ACE inhibitor ramipril and HMG-CoA reductase inhibitor simvastatin. Ramipril significantly reduced the size of atherosclerotic plaques in brachiocephalic arteries, however simvastatin paradoxically stimulated atherogenesis. Both effects occurred without changes in plasma cholesterol. Blood and vascular samples were obtained from the same animals. In the whole blood RNA samples, expression of MMP9, CD14 and IL-1RN reflected pro-and anti-atherogenic drug effects. In the plasma, several proteins, e.g. IL-1beta, IL-18 and MMP9 followed similar trends while protein readout was less sensitive than RNA analysis. CONCLUSION: In this study, we have identified inflammation-related whole blood RNA and plasma protein markers reflecting anti-atherogenic effects of ramipril and pro-atherogenic effects of simwastatin in a mouse model of atherosclerosis. This opens an opportunity for early, non-invasive detection of direct drug effects on atherosclerotic plaques in complex in vivo systems.
authors: Integrative Biology.
authors: Birong
authors: B
authors: Liao
authors: Eileen
authors: E
authors: McCall
authors: Karen
authors: K
authors: Cox
authors: Chung-Wein
authors: CW
authors: Lee
authors: Shuguang
authors: S
authors: Huang
authors: Richard E
authors: RE
authors: Higgs
authors: Li-Chun
authors: LC
authors: Chio
authors: Eugene
authors: E
authors: Zhen
authors: John E
authors: JE
authors: Hale
authors: Nancy K
authors: NK
authors: Jackson
authors: Pamela G
authors: PG
authors: Rutherford
authors: Xiao-di
authors: XD
authors: Huang
authors: Donetta
authors: D
authors: Gifford-Moore
authors: Kwan
authors: K
authors: Hui
authors: Kevin
authors: K
authors: Duffin
authors: Kenneth E
authors: KE
authors: Gould
authors: Mark
authors: M
authors: Rekhter