Doran Amanda C, Ozcan Lale, Cai Bishuang, Zheng Ze, Fredman Gabrielle, Rymond Christina C, Dorweiler Bernhard, Sluimer Judith C, Hsieh Joanne, Kuriakose George, Tall Alan R, Tabas Ira
Department of Medicine, Columbia University, New York, New York, USA.
Department of Molecular and Cellular Physiology, Center for Cardiovascular Sciences, Albany Medical Center, Albany, New York, USA.
J Clin Invest. 2017 Nov 1;127(11):4075-4089. doi: 10.1172/JCI94735. Epub 2017 Oct 3.
Atherosclerosis is the underlying etiology of cardiovascular disease, the leading cause of death worldwide. Atherosclerosis is a heterogeneous disease in which only a small fraction of lesions lead to heart attack, stroke, or sudden cardiac death. A distinct type of plaque containing large necrotic cores with thin fibrous caps often precipitates these acute events. Here, we show that Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages plays a major role in the development of necrotic, thin-capped plaques. Macrophages in necrotic and symptomatic atherosclerotic plaques in humans as well as advanced atherosclerotic lesions in mice demonstrated activation of CaMKII. Western diet-fed LDL receptor-deficient (Ldlr-/-) mice with myeloid-specific deletion of CaMKII had smaller necrotic cores with concomitantly thicker collagen caps. These lesions demonstrated evidence of enhanced efferocytosis, which was associated with increased expression of the macrophage efferocytosis receptor MerTK. Mechanistic studies revealed that CaMKIIγ-deficient macrophages and atherosclerotic lesions lacking myeloid CaMKIIγ had increased expression of the transcription factor ATF6. We determined that ATF6 induces liver X receptor-α (LXRα), an Mertk-inducing transcription factor, and that increased MerTK expression and efferocytosis in CaMKIIγ-deficient macrophages is dependent on LXRα. These findings identify a macrophage CaMKIIγ/ATF6/LXRα/MerTK pathway as a key factor in the development of necrotic atherosclerotic plaques.
动脉粥样硬化是心血管疾病的潜在病因，而心血管疾病是全球主要的死亡原因。动脉粥样硬化是一种异质性疾病，其中只有一小部分病变会导致心脏病发作、中风或心源性猝死。一种含有大的坏死核心和薄纤维帽的独特斑块类型常常引发这些急性事件。在此，我们表明巨噬细胞中的钙/钙调蛋白依赖性蛋白激酶γ（CaMKIIγ）在坏死性薄帽斑块的形成中起主要作用。人类坏死性和有症状动脉粥样硬化斑块以及小鼠晚期动脉粥样硬化病变中的巨噬细胞显示出CaMKII的激活。喂食西方饮食的低密度脂蛋白受体缺陷（Ldlr-/-）小鼠，其髓系特异性缺失CaMKII后，坏死核心较小，同时胶原帽更厚。这些病变显示出吞噬作用增强的证据，这与巨噬细胞吞噬作用受体MerTK的表达增加有关。机制研究表明，缺乏CaMKIIγ的巨噬细胞和缺乏髓系CaMKIIγ的动脉粥样硬化病变中，转录因子ATF6的表达增加。我们确定ATF6诱导肝脏X受体-α（LXRα），一种诱导Mertk的转录因子，并且缺乏CaMKIIγ的巨噬细胞中MerTK表达和吞噬作用的增加依赖于LXRα。这些发现确定了巨噬细胞CaMKIIγ/ATF6/LXRα/MerTK途径是坏死性动脉粥样硬化斑块形成的关键因素。
