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

被引：29

作者：

Devarajan, Asokan ^{[2
]}

Grijalva, Victor R. ^{[2
]}

Bourquard, Noam ^{[2
]}

Meriwether, David, III ^{[3
]}

Imaizumi, Satoshi ^{[2
]}

Shin, Bo-Chul ^{[4
]}

Devaskar, Sherin U. ^{[4
]}

Reddy, Srinivasa T. ^{[1
,2
,3
]}

机构：

[1] Univ Calif Los Angeles, Dept Med Cardiol, Dept Mol & Med Pharmacol, CHS, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Med, Div Cardiol, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Dept Pediat, Neonatal Res Ctr, Div Neonatol & Dev Biol, Los Angeles, CA 90095 USA

来源：

MOLECULAR GENETICS AND METABOLISM | 2012年 / 107卷 / 03期

关键词：

Paraoxonase; 2; Mitochondria; Endoplasmic reticulum; Macrophages; Oxidative stress; E-DEFICIENT MICE; OXIDATIVE STRESS; MITOCHONDRIAL-FUNCTION; ENDOTHELIAL-CELLS; GENE FAMILY; APOPTOSIS; PROTEIN; RECEPTOR; ACTIVATION; PATHWAY;

D O I：

10.1016/j.ymgme.2012.06.020

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. (C) 2012 Elsevier Inc. All rights reserved.

引用

页码：416 / 427

页数：12