Skip to main content
Log in

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

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

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 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. 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.

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Chapter  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    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

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

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719111404605

Keywords

Navigation