title: 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.
abstract: 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.
authors.affiliation: Division of Cardiology, Department of Medicine, University of California Los Angeles, CA 90095, USA.
authors.forename: Asokan
authors.initials: A
authors.lastname: Devarajan
authors.forename: Victor R
authors.initials: VR
authors.lastname: Grijalva
authors.forename: Noam
authors.initials: N
authors.lastname: Bourquard
authors.forename: David
authors.initials: D
authors.lastname: Meriwether
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imaizumi
authors.forename: Bo-Chul
authors.initials: BC
authors.lastname: Shin
authors.forename: Sherin U
authors.initials: SU
authors.lastname: Devaskar
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D017209:Apoptosis; D043303:Aryldialkylphosphatase / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival; D004032:Diet; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D015870:Gene Expression; D006706:Homeostasis; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D018384:Oxidative Stress; D017975:Ruthenium Compounds / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D047028:Macrocyclic Compounds; D010080:Oxazoles; C112020:Ru 360; D017975:Ruthenium Compounds; C108644:xestospongin A; D043303:Aryldialkylphosphatase; D002118:Calcium