Uterine fibroids are characterized by an impaired antioxidant cellular system: potential role of hypoxia in the pathophysiology of uterine fibroids
- 415 Downloads
- 7 Citations
Abstract
Purpose
Fibroids are the most common smooth muscle overgrowth in women. This study determined the expression and the effect of hypoxia on two potent antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT) on human fibroid cells.
Methods
Immortalized human leiomyoma (fibroid) and myometrial cells were subjected to hypoxia (2 % O2, 24 h). Total RNA and cell homogenate were obtained from control and treated cells; CAT and SOD mRNA and activity levels were determined by real-time RT-PCR and ELISA, respectively.
Results
Fibroid cells have significantly lower antioxidant enzymes, SOD and CAT mRNA and activity levels than normal myometrial cells (p < 0.05). Hypoxia treatment significantly increased SOD activity in myometrial cells while significantly decreasing CAT activity in fibroid cells (p < 0.05). There was no significant difference in CAT mRNA levels or activity in response to hypoxia in myometrial cells. Also, there was no significant difference in SOD mRNA levels in response to hypoxia in myometrial cells.
Conclusion
This is the first report to show that uterine fibroids are characterized by an impaired antioxidant cellular enzymatic system. More importantly, our results indicate a role for hypoxia in the modulation of the balance of those enzymes in fibroid and myometrial cells. Collectively, these results shed light on the pathophysiology of fibroids thereby providing potential targets for novel fibroid treatment.
Keywords
Uterine fibroid cells Normal myometrial cells Hypoxia Catalase Superoxide dismutaseReferences
- 1.Agarwal A, Allamaneni SS. Role of free radicals in female reproductive diseases and assisted reproduction. Reprod Biomed Online. 2004;9(3):338–47.PubMedCrossRefGoogle Scholar
- 2.Al-Hendy A, Lee EJ, et al. Gene therapy of uterine leiomyomas: adenovirus-mediated expression of dominant negative estrogen receptor inhibits tumor growth in nude mice. Am J Obstet Gynecol. 2004;191(5):1621–31.PubMedCrossRefGoogle Scholar
- 3.Alpay Z, Saed GM, et al. Female infertility and free radicals: potential role in adhesions and endometriosis. J Soc Gynecol Investig. 2006;13(6):390–8.PubMedCrossRefGoogle Scholar
- 4.Ara C, Kirimlioglu H, et al. Protective effect of melatonin against oxidative stress on adhesion formation in the rat cecum and uterine horn model. Life Sci. 2005;77(12):1341–50.PubMedCrossRefGoogle Scholar
- 5.Augoulea A, Mastorakos G, et al. The role of the oxidative-stress in the endometriosis-related infertility. Gynecol Endocrinol. 2009;25(2):75–81.PubMedCrossRefGoogle Scholar
- 6.Baird DD, Dunson DB, et al. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003;188(1):100–7.PubMedCrossRefGoogle Scholar
- 7.Binda MM, Molinas CR, et al. Reactive oxygen species and adhesion formation: clinical implications in adhesion prevention. Hum Reprod. 2003;18(12):2503–7.PubMedCrossRefGoogle Scholar
- 8.Bulman JC, Ascher SM, et al. Current concepts in uterine fibroid embolization. Radiographics. 2012;32(6):1735–50.PubMedCrossRefGoogle Scholar
- 9.Carney SA, Tahara H, et al. Immortalization of human uterine leiomyoma and myometrial cell lines after induction of telomerase activity: molecular and phenotypic characteristics. Lab Invest. 2002;82(6):719–28.PubMedGoogle Scholar
- 10.Chiaffarino F, Parazzini F, et al. Diet and uterine myomas. Obstet Gynecol. 1999;94(3):395–8.PubMedCrossRefGoogle Scholar
- 11.Chiou JF, Hu ML. Elevated lipid peroxidation and disturbed antioxidant enzyme activities in plasma and erythrocytes of patients with uterine cervicitis and myoma. Clin Biochem. 1999;32(3):189–92.PubMedCrossRefGoogle Scholar
- 12.Evans P, Brunsell S. Uterine fibroid tumors: diagnosis and treatment. Am Fam Physician. 2007;75(10):1503–8.PubMedGoogle Scholar
- 13.Foksinski M, Kotzbach R, et al. The level of typical biomarker of oxidative stress 8-hydroxy-2′-deoxyguanosine is higher in uterine myomas than in control tissues and correlates with the size of the tumor. Free Radic Biol Med. 2000;29(7):597–601.PubMedCrossRefGoogle Scholar
- 14.Fruehauf JP, Meyskens Jr FL. Reactive oxygen species: a breath of life or death? Clin Cancer Res. 2007;13(3):789–94.PubMedCrossRefGoogle Scholar
- 15.Galijasevic S, Saed GM, et al. High dissociation rate constant of ferrous-dioxy complex linked to the catalase-like activity in lactoperoxidase. J Biol Chem. 2004;279(38):39465–70.PubMedCrossRefGoogle Scholar
- 16.Guo Y, Xiao P, et al. How is mRNA expression predictive for protein expression? A correlation study on human circulating monocytes. Acta Biochim Biophys Sin (Shanghai). 2008;40(5):426–36.CrossRefGoogle Scholar
- 17.Halliwell B. Reactive oxygen species in living systems: source, biochemistry, and role in human disease. Am J Med. 1991;91(3C):14S–22S.PubMedCrossRefGoogle Scholar
- 18.Harris AL. Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.PubMedCrossRefGoogle Scholar
- 19.Hassan MH, Salama SA, et al. Adenovirus-mediated delivery of a dominant-negative estrogen receptor gene in uterine leiomyoma cells abrogates estrogen- and progesterone-regulated gene expression. J Clin Endocrinol Metab. 2007;92(10):3949–57.PubMedCrossRefGoogle Scholar
- 20.Inoue M, Sato EF, et al. Mitochondrial generation of reactive oxygen species and its role in aerobic life. Curr Med Chem. 2003;10(23):2495–505.PubMedCrossRefGoogle Scholar
- 21.Kamata H, Hirata H. Redox regulation of cellular signalling. Cell Signal. 1999;11(1):1–14.PubMedCrossRefGoogle Scholar
- 22.Kieran MW, Folkman J, et al. Angiogenesis inhibitors and hypoxia. Nat Med. 2003;9(9):1104. author reply 1104–1105.PubMedCrossRefGoogle Scholar
- 23.Kirkman HN, Gaetani GF. Catalase: a tetrameric enzyme with four tightly bound molecules of NADPH. Proc Natl Acad Sci U S A. 1984;81(14):4343–7.PubMedCrossRefGoogle Scholar
- 24.Linnane AW, Eastwood H. Cellular redox regulation and prooxidant signaling systems: a new perspective on the free radical theory of aging. Ann N Y Acad Sci. 2006;1067:47–55.PubMedCrossRefGoogle Scholar
- 25.Marklund SL. Extracellular superoxide dismutase in human tissues and human cell lines. J Clin Invest. 1984;74(4):1398–403.PubMedCrossRefGoogle Scholar
- 26.Marklund SL, Holme E, et al. Superoxide dismutase in extracellular fluids. Clin Chim Acta. 1982;126(1):41–51.PubMedCrossRefGoogle Scholar
- 27.Nair PM, Park SY, et al. Expression of catalase and glutathione S-transferase genes in Chironomus riparius on exposure to cadmium and nonylphenol. Comp Biochem Physiol C Toxicol Pharmacol. 2011;154(4):399–408.PubMedCrossRefGoogle Scholar
- 28.NIH. 2011. Dietary Supplement Fact Sheet–National Institutes of Health. 2012, From http://ods.od.nih.gov/factsheets/VitaminC-HealthProfessional/.
- 29.Pejic S, Todorovic A, et al. Superoxide dismutase and lipid hydroperoxides in blood and endometrial tissue of patients with benign, hyperplastic and malignant endometrium. An Acad Bras Cienc. 2008;80(3):515–22.PubMedGoogle Scholar
- 30.Rahman K. Studies on free radicals, antioxidants, and co-factors. Clin Interv Aging. 2007;2(2):219–36.PubMedGoogle Scholar
- 31.Sabry M, Al-Hendy A. Innovative oral treatments of uterine leiomyoma. Obstet Gynecol Int. 2012;2012:943635.PubMedGoogle Scholar
- 32.Saed GM, Diamond MP. Hypoxia-induced irreversible up-regulation of type I collagen and transforming growth factor-beta1 in human peritoneal fibroblasts. Fertil Steril. 2002;78(1):144–7.PubMedCrossRefGoogle Scholar
- 33.Saed GM, Diamond MP. Modulation of the expression of tissue plasminogen activator and its inhibitor by hypoxia in human peritoneal and adhesion fibroblasts. Fertil Steril. 2003;79(1):164–8.PubMedCrossRefGoogle Scholar
- 34.Saed GM, Zhang W, et al. Molecular characterization of fibroblasts isolated from human peritoneum and adhesions. Fertil Steril. 2001;75(4):763–8.PubMedCrossRefGoogle Scholar
- 35.Sahin K, Ozercan R, et al. Lycopene supplementation prevents the development of spontaneous smooth muscle tumors of the oviduct in Japanese quail. Nutr Cancer. 2004;50(2):181–9.PubMedCrossRefGoogle Scholar
- 36.Sahin K, Ozercan R, et al. Dietary tomato powder supplementation in the prevention of leiomyoma of the oviduct in the Japanese quail. Nutr Cancer. 2007;59(1):70–5.PubMedCrossRefGoogle Scholar
- 37.Sharan C, Halder SK, et al. Vitamin D inhibits proliferation of human uterine leiomyoma cells via catechol-O-methyltransferase. Fertil Steril. 2011;95(1):247–53.PubMedCrossRefGoogle Scholar
- 38.Singh B, Bhat HK. Superoxide dismutase 3 is induced by antioxidants, inhibits oxidative DNA damage and is associated with inhibition of estrogen-induced breast cancer. Carcinogenesis. 2012;33(12):2601–10.PubMedCrossRefGoogle Scholar
- 39.Stewart EA. Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas. 2009. From www.uptodate.com.
- 40.Trachootham D, Lu W, et al. Redox regulation of cell survival. Antioxid Redox Signal. 2008;10(8):1343–74.PubMedCrossRefGoogle Scholar
- 41.Tuzcu M, Sahin N, et al. The effects of selenium supplementation on the spontaneously occurring fibroid tumors of oviduct, 8-hydroxy-2′-deoxyguanosine levels, and heat shock protein 70 response in Japanese quail. Nutr Cancer. 2010;62(4):495–500.PubMedCrossRefGoogle Scholar
- 42.Ueda S, Masutani H, et al. Redox control of cell death. Antioxid Redox Signal. 2002;4(3):405–14.PubMedCrossRefGoogle Scholar
- 43.Viswanathan M, Hartmann K, et al. Management of uterine fibroids: an update of the evidence. Evid Rep Technol Assess. 2007; (154):1–122 (Full Rep).Google Scholar
- 44.Vural M, Camuzcuoglu H, et al. Oxidative stress and prolidase activity in women with uterine fibroids. J Obstet Gynaecol. 2012;32(1):68–72.PubMedCrossRefGoogle Scholar
- 45.Wight TN, Potter-Perigo S. The extracellular matrix: an active or passive player in fibrosis? Am J Physiol Gastrointest Liver Physiol. 2011;301(6):G950–955.PubMedCrossRefGoogle Scholar
- 46.Wise LA, Radin RG, et al. Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata. Am J Clin Nutr. 2011;94(6):1620–31.PubMedCrossRefGoogle Scholar
- 47.Yoshino O, Hayashi T, et al. Decreased pregnancy rate is linked to abnormal uterine peristalsis caused by intramural fibroids. Hum Reprod. 2010;25(10):2475–9.PubMedCrossRefGoogle Scholar
- 48.Zhou S, Yi T, et al. Hypoxia: the driving force of uterine myometrial stem cells differentiation into leiomyoma cells. Med Hypotheses. 2011;77(6):985–6.PubMedCrossRefGoogle Scholar