Advertisement

Prenatal Nicotine Increases Matrix Metalloproteinase 2 (MMP-2) Expression in Fetal Guinea Pig Hearts

Abstract

This study tested the hypothesis that maternal nicotine ingestion increases matrix metalloproteinase (MMP) expression in fetal hearts, which is mediated by the generation of reactive oxygen species. Timed pregnant guinea pigs were administered either water alone, nicotine (200 μg/mL), N-acetylcysteine (NAC), or nicotine plus NAC in their drinking water for 10 days at 52-day gestation (term = 65 days). Near-term (62 days), anesthetized fetuses were extracted, hearts were excised, and left cardiac ventricles snap frozen for analysis of MMP-2/-9/-13 protein and activity levels. Interstitial collagens were identified by Picrosirius red stain to assess changes in the extracellular matrix. Prenatal nicotine increased active MMP-2 forms and interstitial collagen but had no effect on either pro- or active MMP-9 or MMP-13 forms. In the presence of nicotine, NAC decreased active MMP-2 protein levels and reversed the nicotine-induced increase in collagen staining. We conclude that prenatal nicotine alters MMP-2 expression in fetal hearts that may be mediated by reactive oxygen species generation.

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

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 510

This is the net price. Taxes to be calculated in checkout.

References

  1. 1.

    Substance Abuse and Mental Health Services Administration. Results from the 2004 National Survey on Drug Use and Health: National Findings, Tobacco Use (PDF-1.17MB). Rockville, MD: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2005.

  2. 2.

    Lambers DS, Clark KE. The maternal and fetal physiologic effects of nicotine. Semin Perinatol. 1996;20(2):115–126.

  3. 3.

    Slotkin TA. If nicotine is a developmental neurotoxicant in animal studies, dare we recommend nicotine replacement therapy in pregnant women and adolescents? Neurotoxicol Teratol. 2008;30(1):1–19.

  4. 4.

    Duncan JR, Randall LL, Belliveaur RA, et al. The effect of maternal smoking and drinking during pregnancy upon (3)H-nicotine receptor brainstem binding in infants dying of the sudden infant death syndrome: initial observations in a high risk population. Brain Pathol. 2008;18(1):21–31.

  5. 5.

    Slotkin TA. Prenatal exposure to nicotine: what can we learn from animal models? In: Zagon IS, Slotkin TA, eds. Maternal Substance Abuse and The Developing Nervous System. San Diego, CA: Academic Press; 1992:97–124.

  6. 6.

    Changeux J-P. Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nature Rev Neurosci. 2010;11(6):389–401.

  7. 7.

    Hecht SS. Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nature Rev Cancer. 2003;3(10):733–744.

  8. 8.

    Egleton RD, Brown KC, Dasgupta P. Nicotine acetylcholine receptors in cancer: multiple roles in proliferation and inhibition of apoptosis. Trends Pharmacol Sci. 2008;29(3):151–158.

  9. 9.

    Haass M, Kubler W. Nicotine and sympathetic neurotransmission. Cardiovasc Drugs Ther. 1996;10(6):657–665.

  10. 10.

    Hanna ST. Nicotine effect on cardiovascular system and ion channels. J Cardiovasc Pharmacol. 2006;47(3):348–358.

  11. 11.

    Wang H, Shi H, Zhang L, et al. Nicotine is a potent blocker of the cardiac A-type K+ channels Circulation. 2000;102(10): 1165–1171.

  12. 12.

    Grilli M, Parodi M, Raiteri M, Marchi M. Chronic nicotine differentially affects the function of nicotinic receptor subtypes regulating neurotransmitter release J Neurochem. 2005;93(5): 1353–1360.

  13. 13.

    Jacobs I, Anderson DJ, Surowy CS, Puttfarcken PS. Differential regulate of nicotine receptor-mediated neurotransmitter release following chronic (-)-nicotine administration. Neuropharmacology. 2002;43(5):847–856.

  14. 14.

    Levin ED, Lawrence S, Petro A, Horton K, Seidler FJ, Slotkin TA. Increased nicotine self-administration following prenatal exposure in female rats. Pharmacol Biochem Behav. 2006;85(3):669–674.

  15. 15.

    Maritz GS, Morley CJ, Harding R. Early developmental origins of impaired lung structure and function. Early Hum Dev. 2005;81(9):763–771.

  16. 16.

    Xiao D, Huang X, Lawrence J, Yang S, Zhang L. Fetal and neonatal nicotine exposure differentially regulates vascular contractility in adult male and female offspring J Pharm Exp Ther. 2007;320(2): 654–661.

  17. 17.

    Zhang S, Day I, Ye S. Nicotine induced changes in gene expression by human coronary artery endothelial cells. Atherosclerosis. 2001;154(2):277–283.

  18. 18.

    Lawrence J, Xiao D, Xue Q, Rejali M, Yang S, Zhang L. Prenatal nicotine exposure increases heart susceptibility to ischemia/reperfusion injury in adult offspring. J Pharmacol Exp Ther. 2008;324(1):331–341.

  19. 19.

    Lawrence J, Chen M, Xiong F, et al. Foetal nicotine exposure causes PKC1 gene repression by promoter methylation in rat hearts. Cardiovasc Res. 2011;89(1):89–97.

  20. 20.

    Barros DM, Galhardi FG, Ferreira JLR, et al. The benefits and drawbacks of nicotine exposure in the cortex and hippocampus of old rats. Neuro Toxicol. 2007;28(3):562–568.

  21. 21.

    Bruin JE, Petre MA, Lehman MA, et al. Maternal nicotine exposure increases oxidative stress in the offspring Free Radic Biol Med. 2008;44(11): 1919–1925.

  22. 22.

    Cormier A, Morin C, Zini R, Tillement J-P, Lagrue G. In vitro effects of nicotine on mitochondrial respiration and superoxide anion generation. Brain Res. 2001;900(1):72–79.

  23. 23.

    Fang Q, Sun H, Arrick DM, Mayhan WG. Inhibition of NADPH oxidase improves impaired reactivity of pial arterioles during chronic exposure to nicotine. J Appl Physiol. 2006;100(2):631–636.

  24. 24.

    Jaimes EA, Tian R-X, Raij L. Nicotine: the link between cigarette smoking and the progression of renal injury? Am J Physiol Heart Circ Physiol. 2007;292(1):H76–H82.

  25. 25.

    Deschamps AM, Spinale FG. Pathways of matrix metalloproteinase induction in heart failure: bioactive molecules and transcriptional regulation. Cardiovasc Res. 2006;69(3):666–676.

  26. 26.

    Rutschow S, Li J, Schultheiss H-P, Pauschinger M. Myocardial proteases and matrix remodeling in inflammatory heart disease. Cardiovasc Res. 2006;69(3):646–656.

  27. 27.

    Chow AK, Cena J, Schulz R. Acute actions and novel targets of matrix metalloproteinase in the heart and vasculature. Br J Pharmacol. 2007;152(2):189–205.

  28. 28.

    Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol. 1997;29(7):1422–1431.

  29. 29.

    Jauniaux E, Glubis B, Acharaya G, Thiry P, Rodieck C. Maternal tobacco exposure and cotinine levels in fetal fluids in the first half of pregnancy. Obstet Gynecol. 1999;93(1):25–29.

  30. 30.

    Beloosesky R, Gayle DA, Amidi F, et al. N-acetyl-cysteine suppresses amniotic fluid and placenta inflammatory cytokine responses to lipopolysaccaride in rats. Am J Obstet Gynecol. 2006;194(1):268–273.

  31. 31.

    Demiralay R, Gursan N, Erdem H. The effects of erdosteine, N-acetylcysteine and vitamin E on nicotine-induced apoptosis of cardiac cells. J Appl Toxicol. 2007;27(3):47–54.

  32. 32.

    Langley SC, Kelly FJ. N-acetylcysteine ameliorates hyperoxic lung injury in the preterm guinea pig. Biochem Pharmacol. 1993;45(4):841–846.

  33. 33.

    Ferrari R, Ceconi C, Curello S, et al. Oxygen free radicals and myocardial damage: protective role of thiol-containing agents. Am J Med. 1991;91(3C):95S–105S.

  34. 34.

    Wilkes JM, Clark LE, Herrera JL. Acetaminophen overdose in pregnancy. South Med J. 2005;98(11):1118–1122.

  35. 35.

    Oh C, Dong Y, Liu H, Thompson LP. Intrauterine hypoxia upregulates proinflammatory cytokines and matrix metalloproteinases in fetal guinea pig hearts. Am J Obstet Gynecol. 2008;199(1):78.e1–78.e6. Epub 2008.

  36. 36.

    Junqueira LC, Bignolas G, Brentani RR. Picrosirius staining plus polarization microscopy, a specific method for collagen detection in tissue. Histochem J. 1979;11(4):446–455.

  37. 37.

    Nagase H, Woessner JF. Matrix metalloproteinases. J Biol Chem. 1999;274(31):21491–21494.

  38. 38.

    Nian M, Lee P, Khaper N, Liu P. Inflammatory cytokines and postmyocardial infarction remodeling Circ Res. 2004;94(12): 1543–1553.

  39. 39.

    Lopez B, Gonzalez A, Diez J. Role of matrix metalloproteinase in hypertension-associated cardiac fibrosis. Curr Opin Nephrol Hypertens. 2004;13(2):197–204.

  40. 40.

    Clubb FJ, Bishop SP. Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy. Lab Invest. 1984;50(5):571–577.

  41. 41.

    Baykan A, Narin N, Narin F, Akgun H, Yavasacn S, Saraymen R. The protective effect of melatonin on nicotine-induced myocardial injury in newborn rats whose mothers received nicotine. Anadolu Kardiyol Derg. 2008;8(4):243–248.

  42. 42.

    Li YY, McTiernan CF, Feldman AM. Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovasc Res. 2000;46(2):214–224.

  43. 43.

    Newman MB, Arendash GW, Shytle RD, Bickford PC, Tighe T, Sanberg PR. Nicotine’s oxidative and antioxidant properties in CNS. Life Sci. 2002;71(24):2807–2820.

  44. 44.

    Zhou X, Sheng Y, Yang R, Kong X. Nicotine promotes cardio-myocyte apoptosis via oxidative stress and altered apoptosis-related gene expression. Cardiology. 2010;115(4):243–250.

  45. 45.

    Owasoyo JO, Jay M, Gillespie MN. Impact of nicotine on myocardial neutrophil uptake. Toxicol Appl Pharmacol. 1998;92(1):86–94.

  46. 46.

    Akki A, Zhang M, Murdoch C, Brewer A, Shah AM. NADPH oxidase signaling and cardiac myocyte function. J Mol Cell Cardiol. 2009;47(1):15–22.

  47. 47.

    Yildiz D, Liu YS, Ercal N, Armstrong DW. Comparison of pure nicotine- and smokeless tobacco extract-induced toxicities an oxidative stress. Arch Environ Contam Toxicol. 1999;37(4):434–439.

  48. 48.

    Ra H-J, Parks WC. Control of matrix metalloproteinase catalytic activity. Matrix Biol. 2007;26(8):587–596.

  49. 49.

    Luck W, Nau H, Hansen R, Steldinger R. Extent of nicotine and cotinine transfer to the human fetus, placenta and amniotic fluid of smoking mothers Dev Pharmacol Ther. 1985;8(6): 384–395.

  50. 50.

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

Download references

Author information

Correspondence to Loren P. Thompson PhD.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Thompson, L.P., Liu, H., Evans, L. et al. Prenatal Nicotine Increases Matrix Metalloproteinase 2 (MMP-2) Expression in Fetal Guinea Pig Hearts. Reprod. Sci. 18, 1103–1110 (2011). https://doi.org/10.1177/1933719111404605

Download citation

Keywords

  • collagen
  • cardiac remodeling
  • reactive oxygen species
  • N-acetylcysteine