title: Increased endoplasmic reticulum stress and Nrf2 repression in peripheral blood mononuclear cells of patients with stable coronary artery disease.
abstract: Endoplasmic reticulum (ER) stress is involved in the pathophysiology of atherosclerosis. Insults interfering with ER function lead to the accumulation of unfolded and misfolded proteins in the ER that initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signaling is induced. We evaluated: (1) the UPR and ER-initiated apoptotic signaling in peripheral blood mononuclear cells (PBMCs) of stable coronary artery disease (CAD) patients; (2) PBMC content of oxidation products of phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC); (3) the possible origin of oxPAPC in PBMCs; and (4) the expression of nuclear erythroid-related factor 2 (Nrf2)/antioxidant-related element (ARE), a cellular defense mechanism. Twenty-nine CAD patients and 28 matched controls were enrolled. Expression of glucose-regulated protein 78kDa (GRP78/BiP), as a representative of the UPR, and of C/EBP homologous protein (CHOP), as a representative of ER apoptosis, was significantly higher in CAD than in controls (p<0.01). Concentrations of oxPAPC in PBMCs, in plasma, and in low-density lipoprotein (LDL) were significantly higher in CAD compared to controls (p<0.01). The oxPAPC in PBMCs may derive from circulating ox-LDL. Nrf2/ARE gene expression and circulating and cellular glutathione were significantly lower in CAD compared to controls (p<0.01). In in vitro studies, increasing amounts of oxPAPC induced a dose-dependent increase in CHOP and apoptosis-related protein expression (p<0.01) and a progressive decrease in Nrf2/ARE gene expression (p<0.01). In PBMCs of CAD patients there is an activation of the UPR and ER-initiated apoptotic signaling, possibly related to an abnormal concentration of oxPAPC in PBMCs.
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy. Electronic address: chiaramozzini@libero.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mozzini
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fratta Pasini
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Ulisse
authors.initials: U
authors.lastname: Garbin
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Stranieri
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pasini
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vallerio
authors.affiliation: Section of Internal Medicine, Department of Medicine, University of Verona, 37134 Verona, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Cominacini
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003324:Coronary Artery Disease / Q000097:blood* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D010713:Phosphatidylcholines / Q000097:blood*; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D005609:Free Radicals; C000717247:HSPA5 protein, human; D008077:Lipoproteins, LDL; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010713:Phosphatidylcholines; C099252:oxidized low density lipoprotein; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; D051742:Transcription Factor CHOP
keywords: Apoptosis; Coronary artery disease; ER stress; Free radicals; Nrf2; OxPAPC; UPR