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Phytanic Acid Attenuates Insulin-Like Growth Factor-1 Activity Via Nitric nature publishing group Basic Science Investigation Articles Phytanic acid attenuates insulin-like growth factor-1 activity via nitric oxide-mediated γ-secretase activation in rat aortic smooth muscle cells: possible implications for pathogenesis of infantile Refsum disease Gursev S. Dhaunsi1, Mayra Alsaeid1 and Saghir Akhtar2 BACKGROUND: Infantile Refsum disease (IRD), a peroxisomal cardiovascular anomalies (2,4). In comparison to IRD, an early disease with defective phytanic acid oxidation, causes neuro- onset peroxisomal biogenesis disorder, where patients present logical impairment and development delay. Insulin-like growth developmental delay, mental retardation, neuropathy, sensori- factor-1 (IGF-1) regulates child development and to under- neural hearing loss, osteoporosis (5–8), classical Refsum dis- stand molecular mechanism(s) of IRD, we examined the effect ease is less severe and occurs in late childhood and adults often of phytanic acid (PA) on IGF-1 activity. associated with retinitis pigmentosa, anosmia, deafness, ataxia, METHODS: Bromodeoxyuridine (BrdU) incorporation was and polyneuropathy. Though, PA has been linked, for many measured in rat aortic smooth muscle cell (SMC) cultures fol- years now, to development of certain peroxisomal disorders, yet lowing treatment with fetal bovine serum (FBS), basic fibroblast molecular mechanisms in relation to PA-induced pathogenesis in growth factor (bFGF), platelet-derived growth factor (PDGF) or children have remained unclear. Phytanic acid, a branched fatty IGF-1 in the absence or presence of PA. Gene expression and acid, is now well known to be catabolized in mammalian cells protein contents of IGF-1 receptor (IGF-1R) and PDGF receptor through peroxisome enzyme system (9,10). A major amount of (PDGFR) were examined using quantitative PCR and western circulating phytanic acid in humans comes from dietary sources blotting. such as meats and dairy products (11), and its metabolism was RESULTS: PA inhibited mitogenic activities of FBS, PDGF and recognized to be vital for human health with the identification of IGF-1 with more pronounced effect on IGF-1-induced bromo- peroxisomal disorders, such as Zellweger syndrome and Refsum deoxyuridine (BrdU) incorporation. Palmitic acid or lignoceric disease. Idel and co-workers (12) have reported that supraphysi- acids did not inhibit IGF-1 activity. PA had no effect on PDGFR ological levels of phytanic acid induce nitric oxide-mediated mRNA/protein levels but markedly increased IGF-1R mRNA apoptosis in cultured vascular smooth muscle cells suggesting levels. PA and nitric oxide (NO) markedly decreased IGF-1R pro- thereby that phytanic acid might have a role to play in regulation tein. L-NAME, a NO synthase inhibitor and DAPT, a γ-secretase of smooth muscle cell growth in vivo. During perinatal, neonatal, inhibitor, alleviated PA-induced decrease in IGF-1R protein. and postnatal periods of human development, normal function- Both PA and NO donor increased γ-secretase activity which ing of the vascular system is essential for growth and function of was alleviated by L-NAME. various organs and tissues, and it is not known clearly, as yet, if CONCLUSION: This study demonstrates that PA attenu- phytanic acid has any role to play in growth of vasculature during ates IGF-1 activity possibly through IGF-1R impairment and normal development or disease in children. We reported earlier NO-mediated modulation of γ-secretase activity. that patients with Zellweger syndrome, a peroxisomal disorder with abnormally high serum levels of PA and very long chain fatty acids beside other biochemical defects, have an impaired DNA nfantile Refsum disease (IRD) is a neurometabolic peroxisomal synthesis (13). Growth factors, such as growth hormone and Ibiogenesis disorder characterized by accumulation of supra- Insulin-like growth factors (IGFs), that stimulate DNA synthesis physiological amounts of phytanic acid in tissues and body fluids during mitogenic activities, are key peptides for normal develop- of the patients due to impaired peroxisomal fatty acid oxida- ment of children (14) and a variety of illnesses and metabolic dis- tion (1–3). Children with peroxisomal biogenesis disorders, orders are associated with altered circulating levels of insulin-like such as Zellweger syndrome and IRD have aberrant phytanic growth factor-1 (IGF-1) as well as insulin-growth factor binding acid metabolism and often experience severe clinical complica- proteins (15). Both in vivo and in vitro studies have shown that, tions that range from growth retardation to neurological and besides numerous other biomolecules and metabolites, a variety 1Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait; 2Department of Pharmacology and Toxicology, Faculty of Medicine, Kuwait University, Kuwait. Correspondence: Gursev S. Dhaunsi ([email protected]) Received 31 March 2016; accepted 9 October 2016; advance online publication 11 January 2017. doi:10.1038/pr.2016.258 Copyright © 2017 International Pediatric Research Foundation, Inc. Volume 81 | Number 3 | March 2017 Pediatric ResearcH 531 Articles Dhaunsi et al. of growth factors such as platelet-derived growth factor (PDGF), DMEM-F/12 medium. Phytanic acid concentrations used in this IGF-1, and fibroblast growth factor (FGF) and their receptors, study were chosen based on the reported in vitro studies (12) to avoid cytotoxic effect and ranged from physiological (less than 2.5 µg/ml) are important for angiogenesis and normal growth of vascula- to supraphysiological (more than 2.5 µg/ml) levels but less than those ture (16–18) as well. PDGF has a well-established role in elicit- reported in serum/plasma of Refsum disease patients. Cytotoxic effect ing a proliferative response in vascular smooth muscle cells and, of phytanic acid was checked by counting the percentage of dead like bFGF and IGF-1, much of this proliferative response occurs cells following treatment of cell cultures for 24–72 h. Phytanic acid (0–10 µg/ml) was mixed with α-cyclodextrin-containing Dimethyl through receptor-mediated mitogenic signaling (19). PDGFR sulfoxide (0.001% v/v) and added to the cell cultures in the presence and IGF-1R are membrane associated receptor tyrosine kinases or absence of FBS (5%), PGDF (50 ng/ml), IGF-1 (50 ng/ml), or FGF and binding of a ligand to the extracellular subunit has been (50 ng/ml). Following the addition of experimental agents, cells were ° shown to result in their trans-/activation and signal transduction incubated in cell culture incubator for another 20–24h at 37 C. (20,21). Recent studies have revealed that IGF-1 signaling stimu- BrdU incorporation. DNA synthesis in aortic smooth muscle cells in response to growth factors was assayed via measuring BrdU incor- lates proliferation, survival and differentiation of various cells. In poration in to cellular DNA using kits purchased from Calbiochem. view of the importance of growth factors, particularly, IGF-1, in RNA isolation and reverse transcription. In each experiment, total growth and development of children and, the reported develop- RNA was extracted from cultured smooth muscle cells with RNA ment delay, mental retardation and other anomalies in patients extraction kit based on use of guanidinium thiocyanate, lithium chlo- with phytanic acid metabolism defect, this study was carried out ride, and cesium triflouroacetate. Isolated RNA was of high quality and was used immediately for synthesis of first strand cDNA accord- in vascular smooth muscle cells to examine effect of PA on IGF-1 ing to protocols from Clonetech’s SMART PCR cDNA synthesis kit. activity. Quantitative PCR detection of mRNA for PDGFR and IGF-1R. After the first-strand synthesis, real-time PCR was done using 8 μl METHODS cDNA, 10 μl SYBR green PCR master mix (Bio-Rad Laboratories, Male Wistar Rats (weighing 100–125 g) were used in this study accord- Hercules, CA) and forward and reverse primers (10 μmol/l/ml) ing to the United States National Institute of Health (NIH) guide- (Integrated DNA Technologies, San Diego, CA) in a real-time PCR lines for the Care and Use of Laboratory Animals (NIH Publication system (CFX96; Bio-Rad Laboratories). The primer sequences used No. 85-23, revised in 1996). The study protocols were approved by were IGF-1R; forward 5′-GGGAATGGAGTGCTGTATG-3′, reverse the Research Ethics Committee of Health Sciences Center, Kuwait 5′-CACAGAAGCTTCGTTGAGAA-3′ and PDGFRβ; forward, 5′-C University (MK 01/12). AACATTTCGAGCACCTTTGT-3′, and reverse, 5′-AGGGCACTCC GAAGAGGTAA-3′,. The specificity of the primers was analyzed by Materials running a melting curve. The PCR cycling conditions used were 5 min Bovine serum albumin, penicillin/streptomycin, fetal bovine serum at 95 °C for initial denaturation, 40 cycles of 30 s at 95 °C, 30 s at 58 °C (FBS), elastase, and collagenase were purchased from Sigma Chemical and 30 s at 72 °C. Each real-time PCR was carried out using three Company (St. Louis, MO). Dulbecco's Modified Eagle Medium individual samples in triplicates, and the threshold cycle values were (DMEM)-Ham’s F-12 (1:1) trypsin and Ethylenediaminetetraacetic averaged. Calculations of relative normalized gene expression were acid were from GIBCO (Grand Island, NY). SNAP, and phytanic done using the Bio-Rad CFX manager software. acid were purchased from Sigma Chemical whereas DAPT (N-((3,5- Difluorophenyl)acetyl)-L-alanyl-2-phenyl)glycine-1,1-dimethylethyl Western blotting. Cell homogenates were prepared and SDS- ester) was from Tocris Bioscience, Minneapolis, MN.
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