Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis |
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| Authors: | Ricci Romeo Sumara Grzegorz Sumara Izabela Rozenberg Izabela Kurrer Michael Akhmedov Alexander Hersberger Martin Eriksson Urs Eberli Franz R Becher Burkhard Borén Jan Chen Mian Cybulsky Myron I Moore Kathryn J Freeman Mason W Wagner Erwin F Matter Christian M Lüscher Thomas F |
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| Institution: | Cardiovascular Research, Institute of Physiology, and Division of Cardiology, University Hospital Zurich, CH-8057 Zurich, Switzerland. romeo.ricci@cell.biol.ethz.ca |
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| Abstract: | In vitro studies suggest a role for c-Jun N-terminal kinases (JNKs) in proatherogenic cellular processes. We show that atherosclerosis-prone ApoE-/- mice simultaneously lacking JNK2 (ApoE-/- JNK2-/- mice), but not ApoE-/- JNK1-/- mice, developed less atherosclerosis than do ApoE-/- mice. Pharmacological inhibition of JNK activity efficiently reduced plaque formation. Macrophages lacking JNK2 displayed suppressed foam cell formation caused by defective uptake and degradation of modified lipoproteins and showed increased amounts of the modified lipoprotein-binding and -internalizing scavenger receptor A (SR-A), whose phosphorylation was markedly decreased. Macrophage-restricted deletion of JNK2 was sufficient to decrease atherogenesis. Thus, JNK2-dependent phosphorylation of SR-A promotes uptake of lipids in macrophages, thereby regulating foam cell formation, a critical step in atherogenesis. |
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