Circulating Markers Reflect Both Anti- and Pro-Atherogenic Drug Effects in ApoE-Deficient Mice
Autor: | Li-Chun Chio, Shuguang Huang, Kevin L. Duffin, Xiao-di Huang, Kwan Hui, Chung-Wein Lee, Mark Rekhter, Eugene Zhen, Pamela Rutherford, Birong Liao, Eileen McCall, Donetta Gifford-Moore, Nancy K Jackson, Gould Kenneth Elliot, Karen Cox, Richard E. Higgs, John E. Hale |
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Rok vydání: | 2008 |
Předmět: |
Pharmacology
Ramipril Drug Apolipoprotein E lcsh:R5-920 business.industry media_common.quotation_subject Biochemistry (medical) Bioinformatics Blood proteins Simvastatin In vivo ACE inhibitor Molecular Medicine Medicine lcsh:Medicine (General) business Original Research medicine.drug media_common Whole blood |
Zdroj: | Biomarker Insights, Vol 3 (2008) Biomarker Insights Biomarker Insights, Vol 3, Pp 147-157 (2008) |
ISSN: | 1177-2719 |
Popis: | 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-1β, 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. |
Databáze: | OpenAIRE |
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