Advertisement

Basic Research in Cardiology

, Volume 106, Issue 4, pp 591–602 | Cite as

Chronic cardiac pressure overload induces adrenal medulla hypertrophy and increased catecholamine synthesis

  • Johanna Schneider
  • Achim Lother
  • Lutz Hein
  • Ralf GilsbachEmail author
Original Contribution

Abstract

Increased activity of the sympathetic system is an important feature contributing to the pathogenesis and progression of chronic heart failure. While the mechanisms and consequences of enhanced norepinephrine release from sympathetic nerves have been intensely studied, the role of the adrenal gland in the development of cardiac hypertrophy and progression of heart failure is less well known. Thus, the aim of the present study was to determine the effect of chronic cardiac pressure overload in mice on adrenal medulla structure and function. Cardiac hypertrophy was induced in wild-type mice by transverse aortic constriction (TAC) for 8 weeks. After TAC, the degree of cardiac hypertrophy correlated significantly with adrenal weight and adrenal catecholamine storage. In the medulla, TAC caused an increase in chromaffin cell size but did not result in chromaffin cell proliferation. Ablation of chromaffin α2C-adrenoceptors did not affect adrenal weight or epinephrine synthesis. However, unilateral denervation of the adrenal gland completely prevented adrenal hypertrophy and increased catecholamine synthesis. Transcriptome analysis of microdissected adrenal medulla identified 483 up- and 231 downregulated, well-annotated genes after TAC. Among these genes, G protein-coupled receptor kinases 2 (Grk2) and 6 and phenylethanolamine N-methyltransferase (Pnmt) were significantly upregulated by TAC. In vitro, acetylcholine-induced Pnmt and Grk2 expression as well as enhanced epinephrine content was prevented by inhibition of nicotinic acetylcholine receptors and Ca2+/calmodulin-dependent signaling. Thus, activation of preganglionic sympathetic nerves innervating the adrenal medulla plays an essential role in inducing adrenal hypertrophy, enhanced catecholamine synthesis and induction of Grk2 expression after cardiac pressure overload.

Keywords

Adrenal medulla Epinephrine Sympathetic nervous system Heart failure 

Notes

Acknowledgments

This study was supported by the Deutsche Forschungsgemeinschaft (DFG He 2073/3-1). We thank the EMBL GeneCore (Heidelberg, Germany) staff, especially Vladimir Benes and Tomi Ivacevic, for performing the Affymetrix microarray experiments.

Supplementary material

395_2011_166_MOESM1_ESM.doc (4.2 mb)
Supplementary material 1 (DOC 4.19 mb)
395_2011_166_MOESM2_ESM.pdf (185 kb)
Supplementary material 2 (PDF 185 kb)

References

  1. 1.
    Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, Poole-Wilson PA, Coats AJ (1997) Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 96(2):526–534PubMedGoogle Scholar
  2. 2.
    Anker SD, Steinborn W, Strassburg S (2004) Cardiac cachexia. Ann Med 36(7):518–529. doi: 10.1080/07853890410017467 PubMedCrossRefGoogle Scholar
  3. 3.
    Beetz N, Harrison MD, Brede M, Zong X, Urbanski MJ, Sietmann A, Kaufling J, Barrot M, Seeliger MW, Vieira-Coelho MA, Hamet P, Gaudet D, Seda O, Tremblay J, Kotchen TA, Kaldunski M, Nusing R, Szabo B, Jacob HJ, Cowley AW Jr, Biel M, Stoll M, Lohse MJ, Broeckel U, Hein L (2009) Phosducin influences sympathetic activity and prevents stress-induced hypertension in humans and mice. J Clin Invest 119(12):3597–3612. doi: 10.1172/JCI38433 PubMedGoogle Scholar
  4. 4.
    Braunwald E (2008) Biomarkers in heart failure. N Engl J Med 358(20):2148–2159. doi: 10.1056/NEJMra0800239 PubMedCrossRefGoogle Scholar
  5. 5.
    Braunwald E, Bristow MR (2000) Congestive heart failure: fifty years of progress. Circulation 102(20 Suppl 4):IV14–IV23PubMedGoogle Scholar
  6. 6.
    Brede M, Nagy G, Philipp M, Sorensen JB, Lohse MJ, Hein L (2003) Differential control of adrenal and sympathetic catecholamine release by alpha 2-adrenoceptor subtypes. Mol Endocrinol 17(8):1640–1646. doi: 10.1210/me.2003-0035 PubMedCrossRefGoogle Scholar
  7. 7.
    Brede M, Wiesmann F, Jahns R, Hadamek K, Arnolt C, Neubauer S, Lohse MJ, Hein L (2002) Feedback inhibition of catecholamine release by two different alpha2-adrenoceptor subtypes prevents progression of heart failure. Circulation 106(19):2491–2496PubMedCrossRefGoogle Scholar
  8. 8.
    Ceconi C, Curello S, Ferrari R (1998) Catecholamines: the cardiovascular and neuroendocrine system. Eur Heart J 19(Suppl F):F2–F6Google Scholar
  9. 9.
    CIBIS-II Investigators and Committees (1999) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 353(9146):9–13. doi:S0140673698111819 Google Scholar
  10. 10.
    Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T (1984) Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311(13):819–823PubMedCrossRefGoogle Scholar
  11. 11.
    Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W, Aguzzi A, Fantuzzi G, Hummler E, Unsicker K, Schutz G (1995) Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev 9(13):1608–1621PubMedCrossRefGoogle Scholar
  12. 12.
    (1999) Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353(9169):2001–2007. doi:S0140673699044402
  13. 13.
    Ehrhart-Bornstein M, Bornstein SR, Gonzalez-Hernandez J, Holst JJ, Waterman MR, Scherbaum WA (1995) Sympathoadrenal regulation of adrenocortical steroidogenesis. Endocr Res 21(1–2):13–24PubMedCrossRefGoogle Scholar
  14. 14.
    Evinger MJ, Ernsberger P, Regunathan S, Joh TH, Reis DJ (1994) A single transmitter regulates gene expression through two separate mechanisms: cholinergic regulation of phenylethanolamine N-methyltransferase mRNA via nicotinic and muscarinic pathways. J Neurosci 14(4):2106–2116PubMedGoogle Scholar
  15. 15.
    Frey UH, Lieb W, Erdmann J, Savidou D, Heusch G, Leineweber K, Jakob H, Hense HW, Lowel H, Brockmeyer NH, Schunkert H, Siffert W (2008) Characterization of the GNAQ promoter and association of increased Gq expression with cardiac hypertrophy in humans. Eur Heart J 29(7):888–897. doi: 10.1093/eurheartj/ehm618 PubMedCrossRefGoogle Scholar
  16. 16.
    Gilsbach R, Brede M, Beetz N, Moura E, Muthig V, Gerstner C, Barreto F, Neubauer S, Vieira-Coelho MA, Hein L (2007) Heterozygous alpha 2C-adrenoceptor-deficient mice develop heart failure after transverse aortic constriction. Cardiovasc Res 75(4):728–737. doi: 10.1016/j.cardiores.2007.05.017 PubMedCrossRefGoogle Scholar
  17. 17.
    Gilsbach R, Schneider J, Lother A, Schickinger S, Leemhuis J, Hein L (2010) Sympathetic alpha(2)-adrenoceptors prevent cardiac hypertrophy and fibrosis in mice at baseline but not after chronic pressure overload. Cardiovasc Res 86(3):432–442. doi: 10.1093/cvr/cvq014 PubMedCrossRefGoogle Scholar
  18. 18.
    Gomez F, Lahmame A, de Kloet ER, Armario A (1996) Hypothalamic-pituitary-adrenal response to chronic stress in five inbred rat strains: differential responses are mainly located at the adrenocortical level. Neuroendocrinology 63(4):327–337PubMedCrossRefGoogle Scholar
  19. 19.
    Gosney JR (1985) Adrenal corticomedullary hyperplasia in hypobaric hypoxia. J Pathol 146(1):59–64. doi: 10.1002/path.1711460107 PubMedCrossRefGoogle Scholar
  20. 20.
    Greenberg ME, Ziff EB, Greene LA (1986) Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science 234(4772):80–83PubMedCrossRefGoogle Scholar
  21. 21.
    Grippo AJ, Johnson AK (2009) Stress, depression and cardiovascular dysregulation: a review of neurobiological mechanisms and the integration of research from preclinical disease models. Stress 12(1):1–21. doi: 10.1080/10253890802046281 PubMedCrossRefGoogle Scholar
  22. 22.
    Harvey PW, Sutcliffe C Adrenocortical hypertrophy: establishing cause and toxicological significance. J Appl Toxicol 30(7):617–626. doi: 10.1002/jat.1569
  23. 23.
    Haworth RS, Cuello F, Avkiran M (2011) Regulation by phosphodiesterase isoforms of protein kinase A-mediated attenuation of myocardial protein kinase D activation. Basic Res Cardiol 106(1):51–63. doi: 10.1007/s00395-010-0116-1 PubMedCrossRefGoogle Scholar
  24. 24.
    Johnson AK, Grippo AJ (2006) Sadness and broken hearts: neurohumoral mechanisms and co-morbidity of ischemic heart disease and psychological depression. J Physiol Pharmacol 57(Suppl 11):5–29Google Scholar
  25. 25.
    Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD (1995) Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 26(5):1257–1263. doi: 10.1016/0735-1097(95)00332-0 PubMedCrossRefGoogle Scholar
  26. 26.
    Keating MT, Sanguinetti MC (2001) Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104(4):569–580. doi: S0092-8674(01)00243-4 PubMedCrossRefGoogle Scholar
  27. 27.
    Leineweber K, Heusch G, Schulz R (2007) Regulation and role of the presynaptic and myocardial Na+/H+ exchanger NHE1: effects on the sympathetic nervous system in heart failure. Cardiovasc Drug Rev 25(2):123–131. doi: 10.1111/j.1527-3466.2007.00010.x PubMedCrossRefGoogle Scholar
  28. 28.
    Lymperopoulos A, Rengo G, Funakoshi H, Eckhart AD, Koch WJ (2007) Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat Med 13(3):315–323. doi: 10.1038/nm1553 PubMedCrossRefGoogle Scholar
  29. 29.
    Lymperopoulos A, Rengo G, Gao E, Ebert SN, Dorn GW 2nd, Koch WJ (2010) Reduction of sympathetic activity via adrenal-targeted GRK2 gene deletion attenuates heart failure progression and improves cardiac function after myocardial infarction. J Biol Chem 285(21):16378–16386. doi: 10.1074/jbc.M109.077859 PubMedCrossRefGoogle Scholar
  30. 30.
    Nicholls DP, Onuoha GN, McDowell G, Elborn JS, Riley MS, Nugent AM, Steele IC, Shaw C, Buchanan KD (1996) Neuroendocrine changes in chronic cardiac failure. Basic Res Cardiol 91(Suppl 1):13–20Google Scholar
  31. 31.
    Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH (1996) The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 334(21):1349–1355PubMedCrossRefGoogle Scholar
  32. 32.
    Pool PE (1998) Neurohormonal activation in the treatment of congestive heart failure: basis for new treatments? Cardiology 90(1):1–7. doi: crd90001 PubMedCrossRefGoogle Scholar
  33. 33.
    Rengo G, Leosco D, Zincarelli C, Marchese M, Corbi G, Liccardo D, Filippelli A, Ferrara N, Lisanti MP, Koch WJ, Lymperopoulos A (2010) Adrenal GRK2 lowering is an underlying mechanism for the beneficial sympathetic effects of exercise training in heart failure. Am J Physiol Heart Circ Physiol 298(6):H2032–H2038. doi: 10.1152/ajpheart.00702.2009 PubMedCrossRefGoogle Scholar
  34. 34.
    Richter W, Xie M, Scheitrum C, Krall J, Movsesian MA, Conti M (2011) Conserved expression and functions of PDE4 in rodent and human heart. Basic Res Cardiol 106(2):249–262. doi: 10.1007/s00395-010-0138-8 PubMedCrossRefGoogle Scholar
  35. 35.
    Riegger AJ (1991) Role of neuroendocrine mechanisms in the pathogenesis of heart failure. Basic Res Cardiol 86(Suppl 3):125–131Google Scholar
  36. 36.
    Rockman HA, Koch WJ, Lefkowitz RJ (2002) Seven-transmembrane-spanning receptors and heart function. Nature 415(6868):206–212. doi: 10.1038/415206a PubMedCrossRefGoogle Scholar
  37. 37.
    Sala F, Nistri A, Criado M (2008) Nicotinic acetylcholine receptors of adrenal chromaffin cells. Acta Physiol 192(2):203–212. doi: 10.1111/j.1748-1716.2007.01804.x CrossRefGoogle Scholar
  38. 38.
    Stachowiak MK, Jiang HK, Poisner AM, Tuominen RK, Hong JS (1990) Short and long term regulation of catecholamine biosynthetic enzymes by angiotensin in cultured adrenal medullary cells. Molecular mechanisms and nature of second messenger systems. J Biol Chem 265(8):4694–4702PubMedGoogle Scholar
  39. 39.
    Takahama H, Asanuma H, Sanada S, Fujita M, Sasaki H, Wakeno M, Kim J, Asakura M, Takashima S, Minamino T, Komamura K, Sugimachi M, Kitakaze M (2010) A histamine H receptor blocker ameliorates development of heart failure in dogs independently of beta-adrenergic receptor blockade. Basic Res Cardiol 105(6):787–794. doi: 10.1007/s00395-010-0119-y PubMedCrossRefGoogle Scholar
  40. 40.
    Watson AM, Hood SG, May CN (2006) Mechanisms of sympathetic activation in heart failure. Clin Exp Pharmacol Physiol 33(12):1269–1274. doi: 10.1111/j.1440-1681.2006.04523.x PubMedCrossRefGoogle Scholar
  41. 41.
    Wehrens XH, Marks AR (2003) Altered function and regulation of cardiac ryanodine receptors in cardiac disease. Trends Biochem Sci 28(12):671–678. doi: S096800040300255X PubMedCrossRefGoogle Scholar
  42. 42.
    Wolman M, Cervos-Navarro J, Sampaolo S, Cardesa A (1993) Pathological changes in organs of rats chronically exposed to hypoxia. Development of pulmonary lipidosis. Histol Histopathol 8(2):247–255PubMedGoogle Scholar
  43. 43.
    Womble JR, Larson DF, Copeland JG, Brown BR, Haddox MK, Russell DH (1980) Adrenal medulla denervation prevents stress-induced epinephrine plasma elevation and cardiac hypertrophy. Life Sci 27(24):2417–2420PubMedCrossRefGoogle Scholar
  44. 44.
    Wong DL, Bildstein CL, Siddall B, Lesage A, Yoo YS (1993) Neural regulation of phenylethanolamine N-methyltransferase in vivo: transcriptional and translational changes. Brain Res Mol Brain Res 18(1–2):107–114PubMedCrossRefGoogle Scholar
  45. 45.
    Wong DL, Ebert SN, Morita K (1998) Neural control of phenylethanolamine-N-methyltransferase via cholinergic activation of Egr-I. Adv Pharmacol 42:77–81PubMedCrossRefGoogle Scholar
  46. 46.
    Wurtman RJ (2002) Stress and the adrenocortical control of epinephrine synthesis. Metabolism 51(6 Suppl 1):11–14. doi: ameta0510s11 PubMedCrossRefGoogle Scholar
  47. 47.
    Yamamoto KR (1985) Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet 19:209–252. doi: 10.1146/annurev.ge.19.120185.001233 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Johanna Schneider
    • 1
  • Achim Lother
    • 1
  • Lutz Hein
    • 1
    • 2
  • Ralf Gilsbach
    • 1
    Email author
  1. 1.Institute of Experimental and Clinical Pharmacology and ToxicologyUniversity of FreiburgFreiburgGermany
  2. 2.BIOSS Centre for Biological Signalling StudiesUniversity of FreiburgFreiburgGermany

Personalised recommendations