Skip to main content
Log in

Prenatal Hypoxia Reduces Mitochondrial Protein Levels and Cytochrome c Oxidase Activity in Offspring Guinea Pig Hearts

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Prenatal hypoxia (HPX) reduces mitochondrial cytochrome c oxidase (CCO and COX) activity in fetal guinea pig (GP) hearts. The aim of this study was to quantify the lasting effects of chronic prenatal HPX on cardiac mitochondrial enzyme activity and protein expression in offspring hearts. Pregnant GPs were exposed to either normoxia (NMX) or HPX (10.5%O2) during the last 14 days of pregnancy. Both NMX and HPX fetuses, delivered vaginally, were housed under NMX conditions until 90 days of age. Total RNA and mitochondrial fractions were isolated from hearts of anesthetized NMX and HPX offspring and showed decreased levels of CCO but not medium-chain acyl dehydrogenase activity, protein levels of nuclear- and mitochondrial-encoded COX4 and COX1, respectively, and messenger RNA expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, COX5b, and 4.1 compared to NMX controls. Prenatal HPX may alter mitochondrial function in the offspring by disrupting protein expression associated with the respiratory chain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Hanson MA, Gluckman PD, Developmental origins of health and disease: new insights. Basic Clin Pharmacol Toxicol. 2008; 102(2):90–93.

    Article  CAS  PubMed  Google Scholar 

  2. Barnes SK, Ozanne SE. Pathways linking the early environment to long-term health and lifespan. Prog Biophys Mol Biol. 2011; 106(1):323–336.

    Article  CAS  PubMed  Google Scholar 

  3. Nuyt AM, Alexander BT. Developmental programming and hypertension. Curr Opin Nephrol Hypertens. 2009;18(2):144–152.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Nesterenko TH, Aly H. Fetal and neonatal programming: evidence and clinical implications Am J Perinatol. 2009;26(93): 191–198.

    Article  PubMed  Google Scholar 

  5. Thompson LP, Dong Y. Chronic hypoxia decreases endothelial nitric oxide synthase protein expression in fetal guinea pig hearts. J Soc Gynecol Invest. 2005;12(6):388–395.

    Article  CAS  Google Scholar 

  6. Thompson L, Dong Y, Evans L. Chronic hypoxia increases inducible NOS-derived nitric oxide in fetal guinea pig hearts. Pediatric Res. 2009;65(2):188–192.

    Article  CAS  Google Scholar 

  7. Evans LSC, Liu H, Pinkas GA, Thompson LP. Chronic hypoxia increases peroxynitrite, MMP9 expression, and collagen accumulation in fetal guinea pig hearts. Pediatric Res. 2012;71(1):25–31.

    Article  CAS  Google Scholar 

  8. Oh C, Dong Y, Liu H, Thompson LP. Intrauterine hypoxia upre-gulates proinflammatory cytokines and matrix metalloproteinases in fetal guinea pig hearts. Am J Obstet Gynecol. 2008;199(1):78. e1–6.

    Article  CAS  Google Scholar 

  9. Xue Q, Zhang L. Prenatal hypoxia causes a sex-dependent increase in heart susceptibility to ischemia and reperfusion injury in adult male offspring: role of protein kinase C epsilon. J Pharmacol Exp Ther. 2009;330(2):624–632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dong Y, Hou W, Wei J. Weiner CP. Chronic hypoxemia absent bacterial infection is one cause of the fetal inflammatory response syndrome (FIRS). Repro Sci. 2009;16(6):650–656.

    Article  CAS  Google Scholar 

  11. Dong Y, Yu Z, Sun Y, et al. Chronic fetal hypoxia produces selective brain injury associated with altered nitric oxide synthases. Am J Obstet Gynecol. 2011;204(3):254.el6–28.

    Article  CAS  Google Scholar 

  12. Hashimoto K, Pinkas G, Evans L, Liu H, Al Hasan Y, Thompson LP. Protective effect of N-acetylcysteine on liver damage during chronic intrauterine hypoxia in fetal guinea pig. Repro Sci. 2012; 19(9):1001–1009. doi: 10.1177/1933719112440052.

    Article  Google Scholar 

  13. Camm EJ, Martin-Gronert MS, Wright NL, Hansell JA, Ozanne SE, Giussani DA. Prenatal hypoxia independent of undernutrition promotes molecular markers of insulin resistance in adult offspring. FASEB J. 2011; 25(1): 420–427.

    Article  CAS  PubMed  Google Scholar 

  14. Gentili S, Morrison J, McMillen IC. Transcriptional coregulators in the control of energy homeostasis. Trends in Cell Biol. 2009; 17(6): 292–301.

    Google Scholar 

  15. Peterside IE, Selak AM, Simmons Ra. Imparied oxidative phso-phorylation in hepatic mitochondria in growth-retarded rats. Am J Physiol Endocrin Metab. 2002; 285: E1258–E1266.

    Article  Google Scholar 

  16. Thorn SR, Regnault TR, Brown LD, Rozance PJ, Keng J, Roper M, et al. Intrauterine growth restriction increases fetal hepatic gluconeogenic capacity and reduces messenger ribonucleic acid translation initiation and nutrient sensing in fetal liver and skeletal muscle. Endocrinology. 2009;150(7):3021–3030.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang L. Prenatal hypoxia and cardiac programming. J Soc Gynecol Investig. 2005;12(1):2–13.

    Article  PubMed  Google Scholar 

  18. Rueda Clausen CF, Morton JS, Lopaschuk GD, Davidge ST. Long-term effects of intrauterine growth restriction on cardiac metabolism and susceptibility to ischaemia/reperfusion. Cardio-vasc Res. 2011; 90: 285–294.

    Article  CAS  PubMed  Google Scholar 

  19. Rueda-Clausen CF, Dolinsky VW, Morton JS, Proctor SD, Dyck JRB, Davidge St. Hypoxia-induced intrauterine growth restriction increases the susceptibility of rats to high-fat diet-induced metabolic syndrome. Diabetes. 2011; 60: 507–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lopaschuk GD, Jaswal JS. Energy metabolic phenotype of the cardiomyocyte during development, differentiation, and postnatal maturation. J Cardiovasc Pharmacol. 2010;56(2):130–140.

    Article  CAS  PubMed  Google Scholar 

  21. Onay Besikci A. Regulation of cardiac energy metabolism in newborn. Mol Cell Biochem. 2006;287(1–2):1–11.

    Article  CAS  PubMed  Google Scholar 

  22. Zungu M, Young ME, Stanley WC, Essop MF. Chronic treatment with the peroxisome proliferator-activated receptor α agonist Wy-14,643 attentates myocardial respiratory capacity and contractile function. Mol Cell Biochem. 2009;330(1–2):55–62.

    Article  CAS  PubMed  Google Scholar 

  23. Diaz Moreno I, Garcia Heredia JM, Diaz Quintana A, De la Rosa MA. Cytochrome c signalosome in mitochondria. Eur Biophys J. 2011;40(12):1301–1315.

    Article  CAS  PubMed  Google Scholar 

  24. Nouette Gaulain K, Malgat K, Rocher C, et al. Time course of differential mitochondrial energy metabolism adaptation to chronic hypoxia in right and left ventricles. Cardiovasc Res. 2005; 66(1):132–140.

    Article  CAS  PubMed  Google Scholar 

  25. Petrosillo G, Ruggiero FM, DiVenosa N, Paradies G. Decreased complex III activity in mitochdonria isolated from rat heart subjected to ischemia and reperfusion: P role of reactive oxygen species and cardiolipin. FASEB J. 2003;17(6):714–716.

    Article  CAS  PubMed  Google Scholar 

  26. Nouette Gaulain K, Biais M, Savineau JP, et al. Chronic hypoxia-induced alterations in mitochondrial energy metabolism are not reversible in rat heart ventricles. Can J Physiol Pharmacol. 2011;89(1):58–66.

    Article  CAS  PubMed  Google Scholar 

  27. Al Hasan YM, Evans LC, Pinkas GA, Dabkowski ER, Stanley WC, Thompson LP. Chronic hypoxia impairs Cytochrome Oxidase activity via oxidative stress in selected fetal guinea pig organs. Repro Sci. 2013;20(3):299–307. doi: 10.1177/ 1933719112453509.

    Article  CAS  Google Scholar 

  28. Johnson WT, Anderson CM. Cardiac cytochrome c oxidase activity and contents of subunits 1 and 4 are altered in offspring by low prenatal copper intake by rat dams. J Nutr. 2008;138(7): 1269–1273.

    Article  CAS  PubMed  Google Scholar 

  29. Von Bergen NH, Koppenhafer SL, Spitz DR, Volk KA, Patel SS, Roghair RD. Fetal programming alters reactive oxygen species production in sheep cardiac mitochondria. Clin Sci. 2009; 116(8):659–668.

    Article  Google Scholar 

  30. Li G, Xiao Y, Estrella JL, Ducsay CA, Gilbert RD, Zhang L. Effect of fetal hypoxia on heart susceptibility to ischemia and reperfusion injury in the adult rat. J Soc Gynecol Investig. 2003; 10(5):265–274.

    Article  CAS  PubMed  Google Scholar 

  31. Finck BN, Kelly DP. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest. 2006; 116(3):615–621.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gostimskaya I, Galkin A. Preparation of highly coupled rat heart mitochondria. J Vis Exp. 2010;23(43). doi: 10.3791/2202.

  33. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25(4):402–408.

    CAS  PubMed  Google Scholar 

  34. Dong Y, Thompson LP. Differential expression of eNOS in coronary and cardiac tissue of hypoxic fetal guinea pig hearts. J Soc Gynecol Invest. 2006;13(7):483–490.

    Article  CAS  Google Scholar 

  35. Johnson DM, Geys R, Lissens J, Guns PJ. Drug-induced effects on cardiovascular function pentobarbital anesthetized guinea-pigs: invasive LVP measurements versus the QA interval. J Pharm Toxic Meth. 2012;66(2):152–159.

    Article  CAS  Google Scholar 

  36. Marks L, Borland S, Phip K, et al. The role of the anaesthetised guinea -pig in the preclinical cardiac safety evaluation of drug candidate compounds. Toxic App Pharmacol. 2012;263(2): 171–183.

    Article  CAS  Google Scholar 

  37. Srinivasan S, Avadhani NG. Cytochrome c oxidase dysfunction in oxidative stress. Free Radic Biol Med. 2012;53(6):1252–1263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kelly DP, Scarpulla RC. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 2004;18(4), 357–368.

    Article  CAS  PubMed  Google Scholar 

  39. Scarpulla RC. Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator. Ann N Y Acad Sci. 2008;1147:321–334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fontanesi F, Soto IC, Horn D, Barrientos A. Assembly of mitochondrial cytochrome c-oxidase, a complicated and highly regulated cellular process. Am J Physiol Cell Physiol. 2006;291(6): C1129–C1147.

    Article  CAS  PubMed  Google Scholar 

  41. Scarpulla RC. Nuclear control of respiratory gene expression in mammalian cells. J Cell Biochem. 2006;97(4):673–83.

    Article  CAS  PubMed  Google Scholar 

  42. Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta. 2011;1813(7):1269–1278.

    Article  CAS  PubMed  Google Scholar 

  43. Beauvoit B, Rigoulet M. Regulation of cytochrome c oxidase by adenylic nucleotides. Is oxidative phosphorylation feedback regulated by its end-products? IUBMB life. 2001;52(3–5):143–152.

    Article  CAS  PubMed  Google Scholar 

  44. Napiwotzki J, Kadenbach B. Extramitochondrial ATP/aDP-ratios regulate cytochrome c oxidase activity via binding to the cytosolic domain of subunit IV. Biol Chem. 1998:379(3):335–339.

    Article  CAS  PubMed  Google Scholar 

  45. Yang WL, Iacono L, Tang WM, Chin KV. Novel function of the regulatory subunit of protein kinase A: regulation of cytochrome c oxidase activity and cytochrome c release. Biochem. 1998:37(40): 14175–14180.

    Article  CAS  Google Scholar 

  46. Huigsloot M, Nijtmans LG, Szklarczyk R, et al. A mutation in C2orf64 causes impaired cytochrome c oxidase assembly and mitochondrial cardiomyopathy. Am J Human Gen. 2011;88(4): 488–493.

    Article  CAS  Google Scholar 

  47. Lehman JJ, Kelly DP. Transcriptional activation of energy metabolic switches in the developing and hypertrophied heart. Clin Exp Pharmacol Physiol. 2002;29(4):339–345.

    Article  CAS  PubMed  Google Scholar 

  48. Virbasius JV, Scarpulla RC. Transcriptional activation through ETS domain binding sites in the cytochrome c oxidase subunit IV gene. Mol Cell Biol. 1991 ;11(11):5631–5638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Carter RS, Bhat NK, Basu A, Avadhani NG. The basal promoter elements of murine cytochrome c oxidase subunit IV gene consist of tandemly duplicated ets motifs that bind to GABP-related transcription factors. J Biol Chem. 1992;267(32):23418–23426.

    CAS  PubMed  Google Scholar 

  50. Virbasius JV, Virbasius CA, Scarpulla Re. Identify of GABP with NRF-2, a multisubunit activator of cytochrome oxidase expression, reveals a cellular role for an ETS domain activator of viral promoters. Genes Dev. 1993:7(3):380–392.

    Article  CAS  PubMed  Google Scholar 

  51. Sucharov C, Basu A, Carter RS, Avadhani NG. A novel transcriptional initiator activity of the GABP factor binding ets sequence repeat from the murine cytochrome c oxidase Vb gene. Gene Expr. 1995;5(2):93–111.

    CAS  PubMed  Google Scholar 

  52. Ongwijitwat S, Wong-Riley MT. Is nuclear respiratory factor 2 a master transriptional coordinator for all ten nuclear -endoced cytochrome c oxidase subunits in neurons? Gene. 2005;360(1):65–77.

    Article  CAS  PubMed  Google Scholar 

  53. Andersson U, Scarpulla RC. PGC-1 related coactivator, a novel, serum-inducible coactivator of nuclear respiratory factor 1-dependent transcription I mammalian cells. Mol Cell Biol. 2001;21(ll):3738–3749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gleyzer N, Vercauteren K, Scarpulla RC. Control of mitochondrial transcription specificity factors (TFB1 M and TFB2 M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol Cell Biol. 2005;25(4): 1354–1366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Levert DZ, Radford EJ, Menassa DA, et al. Acclimatization of skeletal muscle mitochondria to high-altitude hypoxia during an ascent of Everest. The FASEB J. 2012;26(4):1431–1441.

    Article  CAS  PubMed  Google Scholar 

  56. Zhao J, Li L, Pei Z, et al. Peroxisome proliferator activated receptor (PPAR)-γ co-activator 1-α and hypoxia induced factor-lα mediate neuro- and vascular protection by hypoxic preconditioning in vitro. Brain Res. 2012;1447:1–8.

    Article  CAS  PubMed  Google Scholar 

  57. Shoag J, Arany Z. Regulation of hypoxia-inducible genes by PGC-1 alpha. Arterioscler Thromb Vase Biol. 2010;30(4): 662–666.

    Article  CAS  PubMed  Google Scholar 

  58. Feige JN, Auwerx J. Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol. 2007;17(6):292–301.

    Article  CAS  PubMed  Google Scholar 

  59. Glass CK. Going nuclear in metabolic and cardiovascular disease. J Clin Invest. 2006;116 (3):556–560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wu Z, Puigserver P, Andersson U, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 1999;98(1):115–124.

    Article  CAS  PubMed  Google Scholar 

  61. Lehman JJ, Boudina S, Banke NH, et al. The transcriptional coactivator PGC-1α is essential for maximal and efficient cardiac mitochondrial fatty acid oxidation and lipid homeostasis. Am J Physiol Heart Circ Physiol. 2008;295(1):H185–H196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science. 2001 ;293(5532): 1068–1070.

    Article  CAS  PubMed  Google Scholar 

  63. Patterson AJ, Chen M, Xue Q, Xiao D, Zhang L. Chronic prenatal hypoxia induces epigenetic programming of PKCε gene repression in rat hearts. Circ Res. 2010;107 (3):365–373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Franco R, Schoneveld O, Georgakilas AG, Panayiotidis MI. Oxidative stress, DNA methylation and carcinogenesis. Cancer Lett. 2008;266(1):6–11.

    Article  CAS  PubMed  Google Scholar 

  65. Nanduri J, Makarenko V, Reddy VD, et al. Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis. Proc Natl Acad Sci U S A. 2012;109(7):2515–2520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Prabhakar NR. Sensing hypoxia: physiology, genetics and epigenetics. J Physiol. 2013;591(pt 9):2245–2257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sanches Roman I, Gomez A, Gomez J, et al. Forty percent methionine restriction lowers DNA methylation, complex I ROS generation, and oxidative damage to mtDNA and mitochondrial proteins in rat heart. J Bioenerg Biomem. 2011;43(6):699–708.

    Article  CAS  Google Scholar 

  68. Ronn T, Poulsen P, Hansson O, et al. Age influences DNA methylation and gene expression of COX7A1 in human skeletal muscle. Diabetologia. 2008;51(7):1159–1168.

    Article  CAS  PubMed  Google Scholar 

  69. Parihar A, Vaccaro P, Ghafourifar P. Nitric oxide irreversibly inhibits cytochrome oxidase at low oxygen concentrations: evidence for inverse oxygen concentration-dependent peroxynitrite formation. Life. 2008;60(1):64–67.

    CAS  PubMed  Google Scholar 

  70. Taylor CT, Moneada S. Nitric oxide, cytochrome c oxidase, and the cellular response to hypoxia. Arterioscler Thromb Vase Biol. 2010;30(4):643–647.

    Article  CAS  PubMed  Google Scholar 

  71. Murray J, Taylor SW, Zhang B, Ghosh SS, Capaldi RA. Oxidative damage to mitochondrial complex I due to peroxynitrite. J Biol Chem. 2003;278(39):37223–37230.

    Article  CAS  PubMed  Google Scholar 

  72. Chen J, Petersen DR, Schenker S, Henderson GI. Formation of malondialdehyde adducts in livers of rats exposed to ethanol: role in ethanol-mediated inhibition of cytochrome c oxidase. Alcoholism Clin Exp Res. 2000;24(4):544–552.

    Article  CAS  Google Scholar 

  73. Zhao S, Xu W, Jiang W, et al. Regulation of cellular metabolism by protein lysine acetylation. Science. 2010;327(5958):1000–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bourque Sl, Gragasin FS, Quon AL, Mansour Y, Morton JS, Davidge ST. Prenatal hypoxia causes long-term alterations in vascular endothelin-1 function in aged male, but not female, offspring. Hypertension. 2013;62(4):753–758.

    Article  CAS  PubMed  Google Scholar 

  75. Kane AD, Herrera EA, Camm EJ, Giussani DA. Vitamin C prevents intrauterine programming of in vivo cardiovascular dysfunction in the rat. Circ J. 2013;77(10):2604–2611.

    Article  CAS  PubMed  Google Scholar 

  76. Rueda Clausen CF, Morton JS, Dolinsky VW, Dyck JR, Davidge ST. Synergistic effects of prenatal hypoxia and postnatal high-fat diet in the development of cardiovascular pathology in young rats. Am J Physiol Regullntegr Comp Physiol. 2012;303(4):R418–R426.

    Article  CAS  PubMed  Google Scholar 

  77. Sack MN, Disch DL, Rockman HA, Kell DP. A role for Sp and nuclear receptor transcription factors in a cardiac hypertrophic growth program. Proc Natl Acad Sci USA. 1997;94(12):6438–6443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Barger PM, Brandt JM, Leone TC, Weinheimer CJ, Kell DP. Deactivation of peroxisome proliferator-activated receptor-α during cardiac hypertrophic growth. J Clin Invest. 2000;105(12): 1723–1730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Loren P. Thompson PhD.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Hasan, Y.M., Pinkas, G.A. & Thompson, L.P. Prenatal Hypoxia Reduces Mitochondrial Protein Levels and Cytochrome c Oxidase Activity in Offspring Guinea Pig Hearts. Reprod. Sci. 21, 883–891 (2014). https://doi.org/10.1177/1933719113518981

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719113518981

Keywords

Navigation