Division of Cardiology, Department of Medicine, University of California Los Angeles, CA 90095, USA.
Mol Genet Metab. 2012 Nov;107(3):416-27. doi: 10.1016/j.ymgme.2012.06.020. Epub 2012 Jul 14.
Paraoxonase 2 deficiency (PON2-def) alters mitochondrial function and exacerbates the development of atherosclerosis in mice. PON2 overexpression protects against ER stress in cell culture. In this paper, we examined the role of PON2 in the unexplored link between ER stress and mitochondrial dysfunction and tested whether restoration of PON2 in macrophages is sufficient to reduce aggravated atherosclerosis in PON2-def/apoE(-/-) mice on a Western diet. ER stress response genes, intracellular calcium levels, and apoptotic nuclei were significantly elevated in PON2-def/apoE(-/-) macrophages compared to apoE(-/-) macrophages in response to ER stressors, but not at the basal level. In contrast, PON2-def/apoE(-/-) macrophages exhibited greater mitochondrial stress at the basal level, which was further worsened in response to ER stressors. There was no difference in ER stress response genes and apoptotic nuclei between apoE(-/-) and PON2-def/apoE(-/-) macrophages when pretreated with xestospongin (which blocks the release of calcium from ER) suggesting that PON2 modulates cell survival and ER stress by maintaining calcium homeostasis. Treatment with a mitochondrial calcium uptake inhibitor, RU360, attenuated ER stressor mediated mitochondrial dysfunction in PON2-def/apoE(-/-) macrophages. CHOP expression (ER stress marker) and apoptotic nuclei were significantly higher in aortic lesions of PON2-def/apoE(-/-) mice compared to apoE(-/-) mice fed a Western diet. Restoration of PON2 in macrophages reduced ER stress, mitochondrial dysfunction and apoptosis in response to ER stressors. Furthermore, restoration of PON2 in macrophages reduced lesional apoptosis and atherosclerosis in PON2-def/apoE(-/-) mice on a Western diet. Our data suggest that macrophage PON2 modulates mechanisms that link ER stress, mitochondrial dysfunction and the development of atherosclerosis.
对氧磷酶 2 缺乏症 (PON2-def) 改变了线粒体功能，并加剧了小鼠动脉粥样硬化的发展。PON2 的过表达可在细胞培养中保护细胞免受内质网应激。在本文中，我们研究了 PON2 在未探索的内质网应激和线粒体功能障碍之间的联系中的作用，并测试了在西方饮食中，巨噬细胞中 PON2 的恢复是否足以减少 PON2-def/apoE(-/-) 小鼠动脉粥样硬化的加剧。与 apoE(-/-) 巨噬细胞相比，PON2-def/apoE(-/-) 巨噬细胞在响应内质网应激源时，内质网应激反应基因、细胞内钙水平和凋亡核显著升高，但在基础水平上没有。相比之下，PON2-def/apoE(-/-) 巨噬细胞在基础水平上表现出更大的线粒体应激，而在响应内质网应激源时则进一步恶化。在用 xestospongin（阻断内质网钙释放）预处理时，apoE(-/-) 和 PON2-def/apoE(-/-) 巨噬细胞之间的内质网应激反应基因和凋亡核没有差异，表明 PON2 通过维持钙稳态来调节细胞存活和内质网应激。用线粒体钙摄取抑制剂 RU360 处理可减轻 PON2-def/apoE(-/-) 巨噬细胞中内质网应激源介导的线粒体功能障碍。PON2-def/apoE(-/-) 小鼠主动脉病变中的 CHOP 表达（内质网应激标志物）和凋亡核明显高于西方饮食喂养的 apoE(-/-) 小鼠。巨噬细胞中 PON2 的恢复减少了对 ER 应激源的 ER 应激、线粒体功能障碍和凋亡。此外，巨噬细胞中 PON2 的恢复减少了 PON2-def/apoE(-/-) 小鼠在西方饮食中的病变凋亡和动脉粥样硬化。我们的数据表明，巨噬细胞 PON2 调节了将内质网应激、线粒体功能障碍和动脉粥样硬化发展联系起来的机制。
