Macrophage paraoxonase 2 regulates calcium homeostasis and cell survival under endoplasmic reticulum stress conditions and is sufficient to prevent the development of aggravated atherosclerosis in paraoxonase 2 deficiency/apoE-/- mice on a Western diet.
Macrophage paraoxonase 2 regulates calcium homeostasis and cell survival under endoplasmic reticulum stress conditions and is sufficient to prevent the development of aggravated atherosclerosis in paraoxonase 2 deficiency/apoE-/- mice on a Western diet.
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DOI：
10.1016/j.ymgme.2012.06.020
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发表时间：
2012-11
影响因子：
3.8
通讯作者：
Reddy, Srinivasa T.
中科院分区：
文献类型：
--
作者：
Devarajan, Asokan;Grijalva, Victor R.;Bourquard, Noam;Meriwether, David, III;Imaizumi, Satoshi;Shin, Bo-Chul;Devaskar, Sherin U.;Reddy, Srinivasa T.
对氧磷酶2缺乏（PON2-def）改变线粒体功能并加剧小鼠动脉粥样硬化的发展。PON2过表达在细胞培养中对内质网应激有保护作用。在本文中，我们研究了PON2在内质网应激和线粒体功能障碍之间未被探索的联系中的作用，并测试了巨噬细胞中PON2的恢复是否足以减轻西式饮食中PON2-def/apoE−/−小鼠的粥样硬化恶化。与apoE−/−巨噬细胞相比，PON2-def/apoE−/−巨噬细胞中内质网应激反应基因、细胞内钙水平和凋亡核在内质网应激反应中显著升高，但在基础水平上没有升高。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，并在内质网应激刺激下进一步恶化。用xestospongin（阻断钙从内质网释放）预处理巨噬细胞后，apoE−/−和PON2-def/apoE−/−巨噬细胞内质网应激反应基因和凋亡核没有差异，这表明PON2通过维持钙稳态来调节细胞存活和内质网应激。线粒体钙摄取抑制剂RU360治疗可减轻内质网应激源介导的PON2-def/apoE−/−巨噬细胞线粒体功能障碍。PON2-def/apoE−/−小鼠主动脉病变中CHOP表达（内质网应激标志物）和凋亡核明显高于apoE−/−小鼠。巨噬细胞PON2的恢复可减轻内质网应激、线粒体功能障碍和细胞凋亡。此外，巨噬细胞中PON2的恢复减少了PON2-def/apoE−/−小鼠的病变细胞凋亡和动脉粥样硬化。我们的数据表明巨噬细胞PON2调节内质网应激、线粒体功能障碍和动脉粥样硬化发展之间的机制。
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 macrophage 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.
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PON2缺陷型小鼠中肝胰岛素信号受损受损：PON2/APOE轴对巨噬细胞炎症反应的新作用。
DOI：
10.1042/bj20101891
发表时间：
2011-05-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Bourquard N;Ng CJ;Reddy ST
通讯作者：
Reddy ST
影响因子：
5.5
作者：
Duan, Yuntao;Gross, Robert A.;Sheu, Shey-Shing
通讯作者：
Sheu, Shey-Shing
DOI：
10.1161/atvbaha.109.198762
发表时间：
2010-02-01
影响因子：
8.7
作者：
Narasimha, Ajay J.;Watanabe, Junji;Reddy, Srinivasa T.
通讯作者：
Reddy, Srinivasa T.
DOI：
10.1007/978-1-60761-362-6_10
发表时间：
2010-01-01
期刊：
NATURAL KILLER CELL PROTOCOLS
影响因子：
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作者：
MacFarlane, Alexander W.;Oesterling, James F.;Campbell, Kerry S.
通讯作者：
Campbell, Kerry S.
DOI：
10.1083/jcb.200904060
发表时间：
2009-09-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Li G;Mongillo M;Chin KT;Harding H;Ron D;Marks AR;Tabas I
通讯作者：
Tabas I