Cardiac response to adrenergic stress differs by sex and across the lifespan

Abstract

The aging heart is well-characterized by a diminished responsiveness to adrenergic activation. However, the precise mechanisms by which age and sex impact adrenergic-mediated cardiac function remain poorly described. In the current investigation, we compared the cardiac response to adrenergic stress to gain mechanistic understanding of how the response to an adrenergic challenge differs by sex and age. Juvenile (4 weeks), adult (4–6 months), and aged (18–20 months) male and female mice were treated with the β-agonist isoproterenol (ISO) for 1 week. ISO-induced morphometric changes were age- and sex-dependent as juvenile and adult mice of both sexes had higher left ventricle weights while aged mice did not increase cardiac mass. Adults increased myocyte cell size and deposited fibrotic matrix in response to ISO, while juvenile and aged animals did not show evidence of hypertrophy or fibrosis. Juvenile females and adults underwent expected changes in systolic function with higher heart rate, ejection fraction, and fractional shortening. However, cardiac function in aged animals was not altered in response to ISO. Transcriptomic analysis identified significant differences in gene expression by age and sex, with few overlapping genes and pathways between groups. Fibrotic and adrenergic signaling pathways were upregulated in adult hearts. Juvenile hearts upregulated genes in the adrenergic pathway with few changes in fibrosis, while aged mice robustly upregulated fibrotic gene expression without changes in adrenergic genes. We suggest that the response to adrenergic stress significantly differs across the lifespan and by sex. Mechanistic definition of these age-related pathways by sex is critical for future research aimed at treating age-related cardiac adrenergic desensitization.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2.
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. 1.

    Ziaeian B, Fonarow GC. Epidemiology and aetiology of heart failure. Nat. Rev. Cardiol. 2016;13:368–78.

    Article  Google Scholar 

  2. 2.

    Shakib S, Clark RA. Heart failure pharmacotherapy and supports in the elderly-a short review. Curr Cardiol Rev. 2016;12:180–5. https://doi.org/10.2174/1573403x12666160622102802.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Bristow MR. The adrenergic nervous system in heart failure. N Engl J Med. 1984;311:850–1. https://doi.org/10.1056/NEJM198409273111310.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Kudej RK, Iwase M, Uechi M, Vatner DE, Oka N, Ishikawa Y, et al. Effects of chronic beta-adrenergic receptor stimulation in mice. J Mol Cell Cardiol. 1997;29:2735–46. https://doi.org/10.1006/jmcc.1997.0508.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Sucharov CC, Hijmans JG, Sobus RD, et al. β-Adrenergic receptor antagonism in mice: a model for pediatric heart disease. J Appl Physiol (Bethesda, Md 1985). 2013;115:979–87. https://doi.org/10.1152/japplphysiol.00627.2013.

    CAS  Article  Google Scholar 

  6. 6.

    Faulx MD, Ernsberger P, Vatner D, Hoffman RD, Lewis W, Strachan R, et al. Strain-dependent beta-adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice. Am J Physiol Heart Circ Physiol. 2005;289:30–H36. https://doi.org/10.1152/ajpheart.00636.2004.

    CAS  Article  Google Scholar 

  7. 7.

    Davies CH, Ferrara N, Harding SE. β-Adrenoceptor function changes with age of subject in myocytes from non-failing human ventricle. Cardiovasc Res. 1996;31:152–6. https://doi.org/10.1016/0008-6363(95)00187-5.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Stratton JR, Cerqueira MD, Schwartz RS, Levy WC, Veith RC, Kahn SE, et al. Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men. Circulation. 1992;86:504–12. https://doi.org/10.1161/01.cir.86.2.504.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Kappert K, Böhm M, Schmieder R, Schumacher H, Teo K, Yusuf S, et al. Impact of sex on cardiovascular outcome in patients at high cardiovascular risk: analysis of the telmisartan randomized assessment study in ACE-intolerant subjects with cardiovascular disease (TRANSCEND) and the ongoing telmisartan alone and in combination with ramipril global end point trial (ONTARGET). Circulation. 2012;126:934–41. https://doi.org/10.1161/CIRCULATIONAHA.111.086660.

    Article  PubMed  Google Scholar 

  10. 10.

    Vizgirda VM, Wahler GM, Sondgeroth KL, Ziolo MT, Schwertz DW. Mechanisms of sex differences in rat cardiac myocyte response to beta-adrenergic stimulation. Am J Physiol Heart Circ Physiol. 2002;282:256–H263. https://doi.org/10.1152/ajpheart.2002.282.1.H256.

    Article  Google Scholar 

  11. 11.

    Toba H, Cannon PL, Yabluchanskiy A, Iyer RP, D’Armiento J, Lindsey ML. Transgenic overexpression of macrophage matrix metalloproteinase-9 exacerbates age-related cardiac hypertrophy, vessel rarefaction, inflammation, and fibrosis. Am J Physiol Heart Circ Physiol. 2017;312:H375–83. https://doi.org/10.1152/ajpheart.00633.2016.

    Article  PubMed  Google Scholar 

  12. 12.

    Faulx MD, Ernsberger P, Vatner D, Hoffman RD, Lewis W, Strachan R, et al. Strain-dependent β-adrenergic receptor function influences myocardial responses to isoproterenol stimulation in mice. Am J Physiol Circ Physiol. 2005;289:H30–6. https://doi.org/10.1152/ajpheart.00636.2004.

    CAS  Article  Google Scholar 

  13. 13.

    Isoyama S, Wei JY, Izumo S, Fort P, Schoen FJ, Grossman W. Effect of age on the development of cardiac hypertrophy produced by aortic constriction in the rat. Circ Res. 1987;61:337–45. https://doi.org/10.1161/01.res.61.3.337.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Mota R, Parry TL, Yates CC, Qiang Z, Eaton SC, Mwiza JM, et al. Increasing cardiomyocyte atrogin-1 reduces aging-associated fibrosis and regulates remodeling in vivo. Am J Pathol. 2018;188:1676–92. https://doi.org/10.1016/j.ajpath.2018.04.007.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Brattelid T, Tveit K, Birkeland JAK, Sjaastad I, Qvigstad E, Krobert KA, et al. Expression of mRNA encoding G protein-coupled receptors involved in congestive heart failure: a quantitative RT-PCR study and the question of normalisation. Basic Res Cardiol. 2007;102:198–208. https://doi.org/10.1007/s00395-007-0648-1.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Ellefsen S, Bliksøen M, Rutkovskiy A, Johansen IB, Kaljusto ML, Nilsson GE, et al. Per-unit-living tissue normalization of real-time RT-PCR data in ischemic rat hearts. Physiol Genomics. 2012;44:651–6. https://doi.org/10.1152/physiolgenomics.00004.2012.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Andrews S (2010) FastQC: a quality control tool for high throughput sequence data.

  18. 18.

    Bushnell B (2014) BBMap: a fast, accurate, splice-aware aligner

  19. 19.

    Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–20. https://doi.org/10.1093/bioinformatics/btu170.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Kim D, Paggi JM, Park C, Bennett C, Salzberg SL. Graph-based genome alignment and genotyping with HISAT2 and HISAT-genotype. Nat Biotechnol. 2019;37:907–15. https://doi.org/10.1038/s41587-019-0201-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Pertea M, Pertea GM, Antonescu CM, Chang TC, Mendell JT, Salzberg SL. StringTie enables improved reconstruction of a transcriptome from RNA-seq reads. Nat Biotechnol. 2015;33:290–5. https://doi.org/10.1038/nbt.3122.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    McCarthy DJ, Chen Y, Smyth GK. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012;40:4288–97. https://doi.org/10.1093/nar/gks042.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40. https://doi.org/10.1093/bioinformatics/btp616.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. Omi A J Integr Biol. 2012. https://doi.org/10.1089/omi.2011.0118.

  25. 25.

    Advanced Research Computing Center (2018) Teton Computing Environment, University of Wyoming, 10.15786/M2FY47

  26. 26.

    Strait JB, Lakatta EG. Aging-associated cardiovascular changes and their relationship to heart failure. Heart Fail Clin. 2012;8:143–64. https://doi.org/10.1016/j.hfc.2011.08.011.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Baxter AJ, Spensley A, Hildreth A, Karimova G, O'Connell JE, Gray CS. β Blockers in older persons with heart failure: tolerability and impact on quality of life. Heart. 2002;88:611–4.

    CAS  Article  Google Scholar 

  28. 28.

    Everitt MD, Sleeper LA, Lu M, Canter CE, Pahl E, Wilkinson JD, et al. Recovery of echocardiographic function in children with idiopathic dilated cardiomyopathy: results from the pediatric cardiomyopathy registry. J Am Coll Cardiol. 2014;63:1405–13. https://doi.org/10.1016/j.jacc.2013.11.059.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Michel FS, Magubane M, Mokotedi L, Norton GR, Woodiwiss AJ. Sex-specific effects of adrenergic-induced left ventricular remodeling in spontaneously hypertensive rats. J Card Fail. 2017;23:161–8. https://doi.org/10.1016/j.cardfail.2016.09.017.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Zhu B, Liu K, Yang C, Qiao Y, Li Z. Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling. Can J Physiol Pharmacol. 2016;94:1349–55. https://doi.org/10.1139/cjpp-2016-0103.

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Grant MKO, Abdelgawad IY, Lewis CA, Seelig D, Zordoky BN. Lack of sexual dimorphism in a mouse model of isoproterenol-induced cardiac dysfunction. PLoS One. 2020;15:e0232507. https://doi.org/10.1371/journal.pone.0232507.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Karbassi E, Monte E, Chapski DJ, Lopez R, Rosa Garrido M, Kim J, et al. Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation. Physiol Genomics. 2016;48:601–15. https://doi.org/10.1152/physiolgenomics.00035.2016.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Farrell ET, Grimes AC, de Lange WJ, Armstrong AE, Ralphe JC. Increased postnatal cardiac hyperplasia precedes cardiomyocyte hypertrophy in a model of hypertrophic cardiomyopathy. Front Physiol. 2017;8:414. https://doi.org/10.3389/fphys.2017.00414.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Patel MD, Mohan J, Schneider C, Bajpai G, Purevjav E, Canter CE, et al. Pediatric and adult dilated cardiomyopathy represent distinct pathological entities. JCI insight. 2017;2:2. https://doi.org/10.1172/jci.insight.94382.

    Article  Google Scholar 

  35. 35.

    Tatman PD, Woulfe KC, Karimpour-Fard A, Jeffrey DA, Jaggers J, Cleveland JC, et al. Pediatric dilated cardiomyopathy hearts display a unique gene expression profile. JCI insight. 2017;2:2. https://doi.org/10.1172/jci.insight.94249.

    Article  Google Scholar 

  36. 36.

    Capasso JM, Malhotra A, Scheuer J, Sonnenblick EH. Myocardial biochemical, contractile, and electrical performance after imposition of hypertension in young and old rats. Circ Res. 1986;58:445–60. https://doi.org/10.1161/01.res.58.4.445.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Raya TE, Gaballa M, Anderson P, Goldman S. Left ventricular function and remodeling after myocardial infarction in aging rats. Am J Physiol. 1997;273:2652–H2658. https://doi.org/10.1152/ajpheart.1997.273.6.H2652.

    Article  Google Scholar 

  38. 38.

    Takahashi T, Schunkert H, Isoyama S, Wei JY, Nadal-Ginard B, Grossman W, et al. Age-related differences in the expression of proto-oncogene and contractile protein genes in response to pressure overload in the rat myocardium. J Clin Invest. 1992;89:939–46. https://doi.org/10.1172/JCI115675.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Ferrara N, Komici K, Corbi G, et al. β-adrenergic receptor responsiveness in aging heart and clinical implications. Front Physiol. 2014;4:396. https://doi.org/10.3389/fphys.2013.00396.

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Cain PA, Ahl R, Hedstrom E, Ugander M, Allansdotter-Johnsson A, Friberg P, et al. Age and gender specific normal values of left ventricular mass, volume and function for gradient echo magnetic resonance imaging: a cross sectional study. BMC Med Imaging. 2009;9:2. https://doi.org/10.1186/1471-2342-9-2.

    Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Klein FJ, Bell S, Runte KE, Lobel R, Ashikaga T, Lerman LO, et al. Heart rate-induced modifications of concentric left ventricular hypertrophy: exploration of a novel therapeutic concept. Am J Physiol Heart Circ Physiol. 2016;311:H1031–9. https://doi.org/10.1152/ajpheart.00301.2016.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Wheatley C, Snyder E, Johnson B, Olson T. Sex differences in cardiovascular function during submaximal exercise in humans. Springerplus. 2014;3:1–13. https://doi.org/10.1186/2193-1801-3-445.

    CAS  Article  Google Scholar 

  43. 43.

    White M, Leenen FH. Effects of age on cardiovascular responses to adrenaline in man. Br J Clin Pharmacol. 1997;43:407–14. https://doi.org/10.1046/j.1365-2125.1997.00561.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Turner MJ, Mier CM, Spina RJ, Schechtman KB, Ehsani AA. Effects of age and gender on the cardiovascular responses to isoproterenol. J Gerontol A Biol Sci Med Sci. 1999;54:B393–403. https://doi.org/10.1093/gerona/54.9.b393.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Prunotto A, Stevenson BJ, Berthonneche C, Schüpfer F, Beckmann JS, Maurer F, et al. RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response. BMC Genomics. 2016;17:717. https://doi.org/10.1186/s12864-016-3059-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Galindo CL, Skinner MA, Errami M, Olson LD, Watson DA, Li J, et al. Transcriptional profile of isoproterenol-induced cardiomyopathy and comparison to exercise-induced cardiac hypertrophy and human cardiac failure. BMC Physiol. 2009;9:23. https://doi.org/10.1186/1472-6793-9-23.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Woulfe KC, Siomos AK, Nguyen H, SooHoo M, Galambos C, Stauffer BL, et al. Fibrosis and fibrotic gene expression in pediatric and adult patients with idiopathic dilated cardiomyopathy. J Card Fail. 2017;23:314–24. https://doi.org/10.1016/j.cardfail.2016.11.006.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Grilo GA, Shaver PR, Stoffel HJ, Morrow CA, Johnson OT, Iyer RP, et al. Age- and sex-dependent differences in extracellular matrix metabolism associate with cardiac functional and structural changes. J Mol Cell Cardiol. 2020;139:62–74. https://doi.org/10.1016/j.yjmcc.2020.01.005.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Kane AE, Bisset ES, Heinze-Milne S, Keller KM, Grandy SA, Howlett SE. Maladaptive changes associated with cardiac aging are sex-specific and graded by frailty and inflammation in C57BL/6 mice. Journals Gerontol Ser A. 2020;76:233–43. https://doi.org/10.1093/gerona/glaa212.

    Article  Google Scholar 

  50. 50.

    Prendergast BJ, Onishi KG, Zucker I. Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci Biobehav Rev. 2014;40:1–5.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Jacob Schlatter and Sydney Polson for technical assistance and the Wyoming INBRE Bioinformatics Core for assistance with data analysis.

Funding

This project was supported by NIH/NIA 1K01 AG058810-01A1 (DRB), NIH/NICHD 2K12 HD057022-11 (KCW), University of Wyoming College of Health Sciences Faculty in Aid (DRB), University of Colorado Lorna Grindlay Moore Faculty Launch Award (KCW), and Institutional Development Award 2-P20-GM-103432.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Danielle R. Bruns.

Ethics declarations

Ethics approval

All animal procedures and protocols were approved by the University of Wyoming Institutional Animal Care and Use Committee (IACUC) prior to the initiation of this study.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(DOCX 1869 kb)

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yusifov, A., Chhatre, V.E., Zumo, J.M. et al. Cardiac response to adrenergic stress differs by sex and across the lifespan. GeroScience (2021). https://doi.org/10.1007/s11357-021-00345-x

Download citation

Keywords

  • Cardiac
  • Sex Differences
  • Adrenergic
  • Juvenile
  • RNA sequencing
  • Lifespan