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
Cardiovascular Research, Institute of Physiology, and Division of Cardiology, University Hospital Zurich, CH-8057 Zurich, Switzerland.
Science. 2004 Nov 26;306(5701):1558-61. doi: 10.1126/science.1101909.
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.
体外研究表明c-Jun氨基末端激酶（JNKs）在促动脉粥样硬化细胞过程中发挥作用。我们发现，易患动脉粥样硬化的ApoE-/-小鼠同时缺乏JNK2（ApoE-/- JNK2-/-小鼠），而非ApoE-/- JNK1-/-小鼠，其动脉粥样硬化的发展程度低于ApoE-/-小鼠。对JNK活性的药理学抑制有效减少了斑块形成。缺乏JNK2的巨噬细胞显示出由修饰脂蛋白摄取和降解缺陷导致的泡沫细胞形成受到抑制，并显示出修饰脂蛋白结合和内化清道夫受体A（SR-A）的量增加，其磷酸化明显降低。巨噬细胞特异性缺失JNK2足以减少动脉粥样硬化的发生。因此，SR-A的JNK2依赖性磷酸化促进巨噬细胞摄取脂质，从而调节泡沫细胞形成，这是动脉粥样硬化发生过程中的关键步骤。
