Skip to main content
SpringerLink
Log in

Sex-specific differences in natriuretic peptide and nitric oxide synthase expression in ANP gene-disrupted mice

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Sex-specific differences in hormone-mediated gene regulation may influence susceptibility to cardiac hypertrophy, a primary risk factor for cardiovascular disease. Under hormonal influence, natriuretic peptide (NP) and nitric oxide synthase (NOS) systems modulate cardio-protective gene programs through common downstream production of cyclic guanosine 3′–5′ monophosphate (cGMP). Ablation of either system can adversely affect cardiac adaptation to stresses and insults. This study elucidates sex-specific differences in cardiac NP and NOS system gene expression and assesses the impact of the estrous cycle on these systems using the atrial natriuretic peptide gene-disrupted (ANP−/−) mouse model. Left ventricular expression of the NP and NOS systems was analyzed using real-time quantitative polymerase chain reaction in 13- to 16-week-old male, proestrous and estrous female ANP+/+ and ANP−/− mice. Left ventricular and plasma cGMP levels were measured to assess the convergent downstream effects of the NP and NOS systems. Regardless of genotype, males had higher expression of the NP system while females had higher expression of the NOS system. In females, transition from proestrus to estrus lowered NOS system expression in ANP+/+ mice while the opposite was observed in ANP−/− mice. No significant changes in left ventricular cGMP levels across gender and genotype were observed. Significantly lower plasma cGMP levels were observed in ANP−/− mice compared to ANP+/+ mice. Regardless of genotype, sex-specific differences in cardiac NP and NOS system expression exist, each sex enlisting a predominant system to conserve downstream cGMP. Estrous cycle-mediated alterations in NOS system expression suggests additional hormone-mediated gene regulation in females.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Johannes J, Bairey Merz CN (2011) Is cardiovascular disease in women inevitable? Cardiol Rev 19:76–80

    Article  PubMed  Google Scholar 

  2. Murphy E, Lagranha C, Deschamps A, Kohr M, Nguyen T, Wong R et al (2011) Mechanism of cardioprotection: what can we learn from females? Pediatr Cardiol 32:354–359

    Article  PubMed  Google Scholar 

  3. Mendelsohn ME (2005) Molecular and cellular basis of cardiovascular gender differences. Science 308:1583–1587

    Article  PubMed  CAS  Google Scholar 

  4. Hayward CS, Kelly RP, Collins P (2000) The roles of gender, the menopause and hormone replacement on cardiovascular function. Cardiovasc Res 46:28–49

    Article  PubMed  CAS  Google Scholar 

  5. Prentice RL (2005) Combined postmenopausal hormone therapy and cardiovascular disease: toward resolving the discrepancy between observational studies and the Women’s Health Initiative clinical trial. Am J Epidemiol 162:404–414

    Article  PubMed  Google Scholar 

  6. Harman SM (2006) Estrogen replacement in menopausal women: recent and current prospective studies, the WHI and the KEEPS. Gend Med 3:254–269

    Article  PubMed  Google Scholar 

  7. Giardina EG (2000) Heart disease in women. Int J Fertil Womens Med 45:350–357

    PubMed  CAS  Google Scholar 

  8. Lorell BH, Carabello BA (2000) Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation 102:470–479

    Article  PubMed  CAS  Google Scholar 

  9. Rajabi M, Kassiotis C, Razeghi P, Taegtmeyer H (2007) Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 12:331–343

    Article  PubMed  CAS  Google Scholar 

  10. Heineke J, Molkentin JD (2006) Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat Rev Mol Cell Biol 7:589–600

    Article  PubMed  CAS  Google Scholar 

  11. Tremblay J, Gerzer R, Vinay P, Pang SC, Béliveau R, Hamet P (1985) The increase of cGMP by atrial natriuretic factor correlates with the distribution of particulate guanylate cyclase. FEBS Lett 181:17–22

    Article  PubMed  CAS  Google Scholar 

  12. Hamet P, Tremblay J, Pang SC, Garcia R, Thibault G, Gutkowska J et al (1984) Effect of native and synthetic atrial natriuretic factor on cyclic GMP. Biochem Biophys Res Commun 123:515–527

    Article  PubMed  CAS  Google Scholar 

  13. Song DL, Kohse KP, Murad F (1988) Brain natriuretic factor. Augmentation of cellular cyclic GMP, activation of particulate guanylate cyclase and receptor binding. FEBS Lett 232:125–129

    Article  PubMed  CAS  Google Scholar 

  14. Waldman SAS, Rapoport RMR, Murad FF (1984) Atrial natriuretic factor selectively activates particulate guanylate cyclase and elevates cyclic GMP in rat tissues. J Biol Chem 259:14332–14334

    PubMed  CAS  Google Scholar 

  15. van den Akker F, Zhang X, Miyagi M, Huo X, Misono KS, Yee VC (2000) Structure of the dimerized hormone-binding domain of a guanylyl-cyclase-coupled receptor. Nature 406:101–104

    Article  PubMed  Google Scholar 

  16. Maack T, Suzuki M, Almeida FA, Nussenzveig D, Scarborough RM, McEnroe GA et al (1987) Physiological role of silent receptors of atrial natriuretic factor. Science 238:675–678

    Article  PubMed  CAS  Google Scholar 

  17. Schmidt HH, Pollock JS, Nakane M, Gorsky LD, Förstermann U, Murad F (1991) Purification of a soluble isoform of guanylyl cyclase-activating-factor synthase. Proc Natl Acad Sci USA 88:365–369

    Article  PubMed  CAS  Google Scholar 

  18. Balligand JL, Kelly RA, Marsden PA, Smith TW, Michel T (1993) Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci USA 90:347–351

    Article  PubMed  CAS  Google Scholar 

  19. Balligand JL, Cannon PJ (1997) Nitric oxide synthases and cardiac muscle. Autocrine and paracrine influences. Arterioscler Thromb Vasc Biol 17:1846–1858

    Article  PubMed  CAS  Google Scholar 

  20. McDonald LJ, Murad F (1996) Nitric oxide and cyclic GMP signaling. Proc Soc Exp Biol Med 211:1–6

    PubMed  CAS  Google Scholar 

  21. Kato T, Muraski J, Chen Y, Tsujita Y, Wall J, Glembotski CC et al (2005) Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and Akt. J Clin Invest 115:2716–2730

    Article  PubMed  CAS  Google Scholar 

  22. Matsui T, Rosenweig A (2005) Convergent signal transduction pathways controlling cardiomyocyte survival and function: the role of PI 3-kinase and Akt. J Mol Cell Cardiol 38:63–71

    Article  PubMed  CAS  Google Scholar 

  23. Manoury B, Montiel V, Balligand JL (2012) Nitric oxide synthase in post-ischaemic remodelling: new pathways and mechanisms. Cardiovasc Res 94:304–315

    Article  PubMed  CAS  Google Scholar 

  24. John SW, Krege JH, Oliver PM, Hagaman JR, Hodgin JB, Pang SC et al (1995) Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension. Science 267:679–681

    Article  PubMed  CAS  Google Scholar 

  25. Angelis E, Tse MY, Pang SC (2005) Interactions between atrial natriuretic peptide and the renin–angiotensin system during salt-sensitivity exhibited by the proANP gene-disrupted mouse. Mol Cell Biochem 276:121–131

    Article  PubMed  CAS  Google Scholar 

  26. Tse MY, Watson JD, Sarda IR, Flynn TG, Pang SC (2001) Expression of B-type natriuretic peptide in atrial natriuretic peptide gene disrupted mice. Mol Cell Biochem 219:99–105

    Article  PubMed  CAS  Google Scholar 

  27. Baylis F (2010) Pregnant women deserve better. Nature 465:689–690

    Article  PubMed  CAS  Google Scholar 

  28. Kim AM, Tingen CM, Woodruff TK (2010) Sex bias in trials and treatment must end. Nature 465:688–689

    Article  PubMed  CAS  Google Scholar 

  29. Zucker I, Beery AK (2010) Males still dominate animal studies. Nature 465:690

    Article  PubMed  CAS  Google Scholar 

  30. McBride SM, Flynn FW, Ren J (2005) Cardiovascular alteration and treatment of hypertension: do men and women differ? Endocrine 28:199–207

    Article  PubMed  CAS  Google Scholar 

  31. Leinwand LA (2003) Sex is a potent modifier of the cardiovascular system. J Clin Invest 112:302–307

    PubMed  CAS  Google Scholar 

  32. Gensini GF, Micheli S, Prisco D, Abbate R (1996) Menopause and risk of cardiovascular disease. Thromb Res 84:1–19

    Article  PubMed  CAS  Google Scholar 

  33. Jankowski M (2005) Pregnancy alters nitric oxide synthase and natriuretic peptide systems in the rat left ventricle. J Endocrinol 184:209–217

    Article  PubMed  CAS  Google Scholar 

  34. Madhani M, Scotland RS, MacAllister RJ, Hobbs AJ (2003) Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling. Br J Pharmacol 139:1289–1296

    Article  PubMed  CAS  Google Scholar 

  35. Kotlo KU, Rasenick MM, Danziger RS (2009) Evidence for cross-talk between atrial natriuretic peptide and nitric oxide receptors. Mol Cell Biochem 338:183–189

    Article  PubMed  Google Scholar 

  36. Wang TJ, Larson MG, Levy D, Leip EP, Benjamin EJ, Wilson PWF et al (2002) Impact of age and sex on plasma natriuretic peptide levels in healthy adults. Am J Cardiol 90:254–258

    Article  PubMed  CAS  Google Scholar 

  37. Raizada V, Thakore K, Luo W, McGuire PG (2001) Cardiac chamber-specific alterations of ANP and BNP expression with advancing age and with systemic hypertension. Mol Cell Biochem 216:137–140

    Article  PubMed  CAS  Google Scholar 

  38. Gyurko R, Kuhlencordt P, Fishman MC, Huang PL (2000) Modulation of mouse cardiac function in vivo by eNOS and ANP. Am J Physiol Heart Circ Physiol 278:H971–H981

    PubMed  CAS  Google Scholar 

  39. Li W, Mital S, Ojaimi C, Csiszar A, Kaley G, Hintze TH (2004) Premature death and age-related cardiac dysfunction in male eNOS-knockout mice. J Mol Cell Cardiol 37:671–680

    Article  PubMed  CAS  Google Scholar 

  40. Jankowski M, Reis AM, Mukaddam-Daher S, Dam TV, Farookhi R, Gutkowska J (1997) C-type natriuretic peptide and the guanylyl cyclase receptors in the rat ovary are modulated by the estrous cycle. Biol Reprod 56:59–66

    Article  PubMed  CAS  Google Scholar 

  41. Reis AM, Jankowski M, Mukaddam-Daher S, Tremblay J, Dam TV, Gutkowska J (1997) Regulation of the natriuretic peptide system in rat uterus during the estrous cycle. J Endocrinol 153:345–355

    Article  PubMed  CAS  Google Scholar 

  42. Noubani AA, Farookhi RR, Gutkowska JJ (2000) B-type natriuretic peptide receptor expression and activity are hormonally regulated in rat ovarian cells. Endocrinology 141:551–559

    Article  PubMed  CAS  Google Scholar 

  43. Puri V, Cui L, Liverman CS, Roby KF, Klein RM, Welch KMA et al (2005) Ovarian steroids regulate neuropeptides in the trigeminal ganglion. Neuropeptides 39:409–417

    Article  PubMed  CAS  Google Scholar 

  44. Sica M, Martini M, Viglietti-Panzica C, Panzica G (2009) Estrous cycle influences the expression of neuronal nitric oxide synthase in the hypothalamus and limbic system of female mice. BMC Neurosci 10:78

    Article  PubMed  Google Scholar 

  45. Kleinert H, Wallerath T, Euchenhofer C, Ihrig-Biedert I, Li H, Förstermann U (1998) Estrogens increase transcription of the human endothelial NO synthase gene: analysis of the transcription factors involved. Hypertension 31:582–588

    Article  PubMed  CAS  Google Scholar 

  46. Nuedling S, Kahlert S, Loebbert K, Doevendans PA, Meyer R, Vetter H et al (1999) 17 Beta-estradiol stimulates expression of endothelial and inducible NO synthase in rat myocardium in vitro and in vivo. Cardiovasc Res 43:666–674

    Article  PubMed  CAS  Google Scholar 

  47. Patten RD, Pourati I, Aronovitz MJ, Alsheikh-Ali A, Eder S, Force T et al (2008) 17 Beta-estradiol differentially affects left ventricular and cardiomyocyte hypertrophy following myocardial infarction and pressure overload. J Card Fail 14:245–253

    Article  PubMed  CAS  Google Scholar 

  48. Bhuiyan MS, Shioda N, Fukunaga K (2007) Ovariectomy augments pressure overload-induced hypertrophy associated with changes in Akt and nitric oxide synthase signaling pathways in female rats. Am J Physiol Endocrinol Metab 293:E1606–E1614

    Article  PubMed  CAS  Google Scholar 

  49. Sangaralingham SJ, Tse MY, Pang SC (2007) Estrogen delays the progression of salt-induced cardiac hypertrophy by influencing the renin–angiotensin system in heterozygous proANP gene-disrupted mice. Mol Cell Biochem 306:221–230

    Article  PubMed  CAS  Google Scholar 

  50. Sangaralingham SJ, Tse MY, Pang SC (2007) Estrogen protects against the development of salt-induced cardiac hypertrophy in heterozygous proANP gene-disrupted mice. J Endocrinol 194:143–152

    Article  PubMed  CAS  Google Scholar 

  51. Fischmeister R, Castro LRV, Abi-Gerges A, Rochais F, Jurevicius J, Leroy J et al (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases. Circ Res 99:816–828

    Article  PubMed  CAS  Google Scholar 

  52. Pimenta E (2012) Hypertension in women. Hypertens Res 35:148–152

    Article  PubMed  CAS  Google Scholar 

  53. Engberding N, Wenger NK (2012) Management of hypertension in women. Hypertens Res 35:251–260

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors wish to thank Dr. Louise Winn for reviewing the manuscript and providing helpful comments and suggestions. PGW is a recipient of the R.J. Wilson Graduate Award. DWJA was supported by a Master’s Studentship Award from the Heart and Stroke Foundation of Ontario. EPAB was a recipient of the Heart and Stroke Foundation John Schultz Science Student Scholarship. Financial support from the Heart and Stroke Foundation of Ontario to SCP (Grant #: NA7297) is gratefully acknowledged. The purchase of the Roche Lightcycler 480 II was provided by an equipment grant from Canada Foundation for Innovation (CFI) to Drs. Amsden, Waldman and Pang.

Conflict of interest

There is no conflict of interest that could be perceived as prejudicing the impartiality of the research presented.

Author information

Authors and Affiliations

  1. Department of Biomedical and Molecular Sciences, Queen’s University, Room 850, Botterell Hall, Kingston, ON, K7L 3N6, Canada

    Philip G. Wong, David W. J. Armstrong, M. Yat Tse, Emily P. A. Brander & Stephen C. Pang

Authors
  1. Philip G. Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David W. J. Armstrong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Yat Tse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emily P. A. Brander
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Stephen C. Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen C. Pang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, P.G., Armstrong, D.W.J., Tse, M.Y. et al. Sex-specific differences in natriuretic peptide and nitric oxide synthase expression in ANP gene-disrupted mice. Mol Cell Biochem 374, 125–135 (2013). https://doi.org/10.1007/s11010-012-1511-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-012-1511-8

Keywords

Search

Navigation