title: Phytochemical indicaxanthin suppresses 7-ketocholesterol-induced THP-1 cell apoptosis by preventing cytosolic Ca(2+) increase and oxidative stress.
abstract: 7-Ketocholesterol (7-KC)-induced apoptosis of macrophages is considered a key event in the development of human atheromas. In the present study, the effect of indicaxanthin (Ind), a bioactive pigment from cactus pear fruit, on 7-KC-induced apoptosis of human monocyte/macrophage THP-1 cells was investigated. A pathophysiological condition was simulated by using amounts of 7-KC that can be reached in human atheromatous plaque. Ind was assayed within a micromolar concentration range, consistent with its plasma level after dietary supplementation with cactus pear fruit. Pro-apoptotic effects of 7-KC were assessed by cell cycle arrest, exposure of phosphatidylserine at the plasma membrane, variation of nuclear morphology, decrease of mitochondrial trans-membrane potential, activation of Bcl-2 antagonist of cell death and poly(ADP-ribose) polymerase-1 cleavage. Kinetic measurements within 24 h showed early formation of intracellular reactive oxygen species over basal levels, preceding NADPH oxidase-4 (NOX-4) over-expression and elevation of cytosolic Ca²⁺, with progressive depletion of total thiols. 7-KC-dependent activation of the redox-sensitive NF-κB was observed. Co-incubation of 2·5 μm of Ind completely prevented 7-KC-induced pro-apoptotic events. The effects of Ind may be ascribed to inhibition of NOX-4 basal activity and over-expression, inhibition of NF-κB activation, maintaining cell redox balance and Ca homeostasis, with prevention of mitochondrial damage and consequently apoptosis. The findings suggest that Ind, a highly bioavailable dietary phytochemical, may exert protective effects against atherogenetic toxicity of 7-KC at a concentration of nutritional interest.
authors.affiliation: Dipartimento Scienze e Tecnologie Molecolari e Biomolecolari, Università di Palermo, Palermo, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Tesoriere
authors.forename: Alessandro
authors.initials: A
authors.lastname: Attanzio
authors.forename: Mario
authors.initials: M
authors.lastname: Allegra
authors.forename: Carla
authors.initials: C
authors.lastname: Gentile
authors.forename: Maria A
authors.initials: MA
authors.lastname: Livrea
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000517:prevention & control; D050860:Betaxanthins / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D019587:Dietary Supplements; D005638:Fruit; D006801:Humans; D007653:Ketocholesterols / Q000009:adverse effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D029747:Opuntia / Q000737:chemistry*; D018384:Oxidative Stress / Q000187:drug effects*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D058226:Plaque, Atherosclerotic / Q000517:prevention & control; D011725:Pyridines / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D050860:Betaxanthins; D007653:Ketocholesterols; D016328:NF-kappa B; D010936:Plant Extracts; D011725:Pyridines; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; C469628:indicaxanthin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C003001:7-ketocholesterol; D002118:Calcium