Skip to main content

Advertisement

Log in

Endogenous endothelin 1 mediates angiotensin II-induced hypertrophy in electrically paced cardiac myocytes through EGFR transactivation, reactive oxygen species and NHE-1

  • Molecular and cellular mechanisms of disease
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Emerging evidence supports a key role for endothelin-1 (ET-1) and the transactivation of the epidermal growth factor receptor (EGFR) in angiotensin II (Ang II) action. We aim to determine the potential role played by endogenous ET-1, EGFR transactivation and redox-dependent sodium hydrogen exchanger-1 (NHE-1) activation in the hypertrophic response to Ang II of cardiac myocytes. Electrically paced adult cat cardiomyocytes were placed in culture and stimulated with 1 nmol l-1 Ang II or 5 nmol l-1 ET-1. Ang II increased ~45 % cell surface area (CSA) and ~37 % [3H]-phenylalanine incorporation, effects that were blocked not only by losartan (Los) but also by BQ123 (AT1 and ETA receptor antagonists, respectively). Moreover, Ang II significantly increased ET-1 messenger RNA (mRNA) expression. ET-1 similarly increased myocyte CSA and protein synthesis, actions prevented by the reactive oxygen species scavenger MPG or the NHE-1 inhibitor cariporide (carip). ET-1 increased the phosphorylation of the redox-sensitive ERK1/2-p90RSK kinases, main activators of the NHE-1. This effect was prevented by MPG and the antagonist of EGFR, AG1478. Ang II, ET-1 and EGF increased myocardial superoxide production (187 ± 9 %, 149 ± 8 % and 163.7 ± 6 % of control, respectively) and AG1478 inhibited these effects. Interestingly, Los inhibited only Ang II whilst BQ123 cancelled both Ang II and ET-1 actions, supporting the sequential and unidirectional activation of AT1, ETA and EGFR. Based on the present evidence, we propose that endogenous ET-1 mediates the hypertrophic response to Ang II by a mechanism that involves EGFR transactivation and redox-dependent activation of the ERK1/2-p90RSK and NHE-1 in adult cardiomyocytes.

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.

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

Similar content being viewed by others

References

  1. Aiello EA, Cingolani HE (2001) Angiotensin II stimulates cardiac L-type Ca(2+) current by a Ca(2+)- and protein kinase C-dependent mechanism. Am J Physiol 280(4):H1528–H1536

    CAS  Google Scholar 

  2. Aiello EA, Villa-Abrille MC, Dulce RA, Cingolani HE, Perez NG (2005) Endothelin-1 stimulates the Na+/Ca2+ exchanger reverse mode through intracellular Na+ (Na+ i)-dependent and Na+ i-independent pathways. Hypertension 45(2):288–293

    Article  CAS  PubMed  Google Scholar 

  3. Anderson HD, Wang F, Gardner DG (2004) Role of the epidermal growth factor receptor in signaling strain-dependent activation of the brain natriuretic peptide gene. J Biol Chem 279(10):9287–9297

    Article  CAS  PubMed  Google Scholar 

  4. Anilkumar N, Sirker A, Shah AM (2009) Redox sensitive signaling pathways in cardiac remodeling, hypertrophy and failure. Front Biosci 14:3168–3187

    Article  CAS  Google Scholar 

  5. Bendall JK, Cave AC, Heymes C, Gall N, Shah AM (2002) Pivotal role of a gp91(phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 105(3):293–296

    Article  CAS  PubMed  Google Scholar 

  6. Berger HJ, Prasad SK, Davidoff AJ, Pimental D, Ellingsen O, Marsh JD, Smith TW, Kelly RA (1994) Continual electric field stimulation preserves contractile function of adult ventricular myocytes in primary culture. Am J Physiol 266(1 Pt 2):H341–H349

    CAS  PubMed  Google Scholar 

  7. Caldiz CI, Garciarena CD, Dulce RA, Novaretto LP, Yeves AM, Ennis IL, Cingolani HE, Chiappe de Cingolani G, Perez NG (2007) Mitochondrial reactive oxygen species activate the slow force response to stretch in feline myocardium. J Physiol 584(Pt 3):895–905

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Cingolani HE, Ennis IL (2007) Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation 115(9):1090–1100

    Article  PubMed  Google Scholar 

  9. Cingolani HE, Ennis IL, Aiello EA, Perez NG (2011) Role of autocrine/paracrine mechanisms in response to myocardial strain. Pflugers Arch 462(1):29–38

    Article  CAS  PubMed  Google Scholar 

  10. Cingolani HE, Perez NG, Aiello EA, Ennis IL, Garciarena CD, Villa-Abrille MC, Dulce RA, Caldiz CI, Yeves AM, Correa MV, Nolly MB, Chiappe de Cingolani G (2008) Early signals after stretch leading to cardiac hypertrophy. Key role of NHE-1. Front Biosci 13:7096–7114

    Article  CAS  PubMed  Google Scholar 

  11. Cingolani HE, Perez NG, Caldiz CI, Garciarena CD, De Giusti VC, Correa MV, Villa-Abrille MC, Yeves AM, Ennis IL, Chiappe de Cingolani G, Aiello EA (2010) Early hypertrophic signals after myocardial stretch. Role of reactive oxygen species and the sodium/hydrogen exchanger. In: Kamkin A, Kiseleva I (eds) Mechanosensitivity in cells and tissues: mechanosensitivy of the heart. Springer, Moscow, pp 327–371

    Google Scholar 

  12. Cingolani HE, Villa-Abrille MC, Cornelli M, Nolly A, Ennis IL, Garciarena C, Suburo AM, Torbidoni V, Correa MV, Camilionde Hurtado MC, Aiello EA (2006) The positive inotropic effect of angiotensin II: role of endothelin-1 and reactive oxygen species. Hypertension 47(4):727–734

    Article  CAS  PubMed  Google Scholar 

  13. Cingolani OH, Perez NG, Mosca SM, Schinella GR, Console GM, Ennis IL, Escudero EM, Cingolani HE (2010) AT1 receptor blockade with losartan prevents maladaptive hypertrophy in pressure overload by inhibiting ROS release. Hypertension 56:e119

    Google Scholar 

  14. Cooper GT, Mercer WE, Hoober JK, Gordon PR, Kent RL, Lauva IK, Marino TA (1986) Load regulation of the properties of adult feline cardiocytes. The role of substrate adhesion. Circ Res 58(5):692–705

    Article  PubMed  Google Scholar 

  15. Chan HW, Jenkins A, Pipolo L, Hannan RD, Thomas WG, Smith NJ (2006) Effect of dominant-negative epidermal growth factor receptors on cardiomyocyte hypertrophy. J Receptor Signal Trans Res 26(5–6):659–677

    CAS  Google Scholar 

  16. Dai DF, Rabinovitch P Mitochondrial oxidative stress mediates induction of autophagy and hypertrophy in angiotensin-II treated mouse hearts. Autophagy 7(8):917–918

  17. De Giusti VC, Nolly MB, Yeves AM, Caldiz CI, Villa-Abrille MC, de Cingolani GE C, Ennis IL, Cingolani HE, Aiello EA (2011) Aldosterone stimulates the cardiac Na(+)/H(+) exchanger via transactivation of the epidermal growth factor receptor. Hypertension 58(5):912–919. doi:10.1161/HYPERTENSIONAHA.111.176024

    Article  PubMed  Google Scholar 

  18. Drugge ED, Rosen MR, Robinson RB (1985) Neuronal regulation of the development of the alpha-adrenergic chronotropic response in the rat heart. Circ Res 57(3):415–423

    Article  CAS  PubMed  Google Scholar 

  19. Dubus I, Rappaport L, Barrieux A, Lompre AM, Schwartz K, Samuel JL (1993) Contractile protein gene expression in serum-free cultured adult rat cardiac myocytes. Pflugers Arch 423(5–6):455–461

    Article  CAS  PubMed  Google Scholar 

  20. Ellingsen O, Davidoff AJ, Prasad SK, Berger HJ, Springhorn JP, Marsh JD, Kelly RA, Smith TW (1993) Adult rat ventricular myocytes cultured in defined medium: phenotype and electromechanical function. Am J Physiol 265(2 Pt 2):H747–H754

    CAS  PubMed  Google Scholar 

  21. Ennis IL, Garciarena CD, Escudero EM, Perez NG, Dulce RA, Camilion de Hurtado MC, Cingolani HE (2007) Normalization of the calcineurin pathway underlies the regression of hypertensive hypertrophy induced by Na+/H+ exchanger-1 (NHE-1) inhibition. Can J Physiol Pharmacol 85(3–4):301–310

    CAS  PubMed  Google Scholar 

  22. Ennis IL, Garciarena CD, Perez NG, Dulce RA, Camilion de Hurtado MC, Cingolani HE (2005) Endothelin isoforms and the response to myocardial stretch. Am J Physiol 288(6):H2925–H2930

    CAS  Google Scholar 

  23. Escobar AL, Ribeiro-Costa R, Villalba-Galea C, Zoghbi ME, Perez CG, Mejia-Alvarez R (2004) Developmental changes of intracellular Ca2+ transients in beating rat hearts. Am J Physiol 286(3):H971–H978

    CAS  Google Scholar 

  24. Essick EE, Ouchi N, Wilson RM, Ohashi K, Ghobrial J, Shibata R, Pimentel DR, Sam F Adiponectin mediates cardioprotection in oxidative stress-induced cardiac myocyte remodeling. Am J Physiol Heart Circ Physiol 301(3):H984–H993

  25. Factor SM, Butany J, Sole MJ, Wigle ED, Williams WC, Rojkind M (1991) Pathologic fibrosis and matrix connective tissue in the subaortic myocardium of patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 17(6):1343–1351

    Article  CAS  PubMed  Google Scholar 

  26. Fox PR, Liu SK, Maron BJ (1995) Echocardiographic assessment of spontaneously occurring feline hypertrophic cardiomyopathy. An animal model of human disease. Circulation 92(9):2645–2651

    Article  CAS  PubMed  Google Scholar 

  27. Garciarena CD, Caldiz CI, Correa MV, Schinella GR, Mosca SM, Chiappe de Cingolani GE, Cingolani HE, Ennis IL (2008) Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action. J Appl Physiol 105(6):1706–1713

    Article  CAS  PubMed  Google Scholar 

  28. Han HM, Robinson RB, Bilezikian JP, Steinberg SF (1989) Developmental changes in guanine nucleotide regulatory proteins in the rat myocardial alpha 1-adrenergic receptor complex. Circ Res 65(6):1763–1773

    Article  CAS  PubMed  Google Scholar 

  29. Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Murumo F, Hiroe M (1993) Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 92(1):398–403

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Kagiyama S, Eguchi S, Frank GD, Inagami T, Zhang YC, Phillips MI (2002) Angiotensin II-induced cardiac hypertrophy and hypertension are attenuated by epidermal growth factor receptor antisense. Circulation 106(8):909–912

    Article  CAS  PubMed  Google Scholar 

  31. Karmazyn M, Kilic A, Javadov S (2008) The role of NHE-1 in myocardial hypertrophy and remodelling. J Mol Cell Cardiol 44(4):647–653

    Article  CAS  PubMed  Google Scholar 

  32. Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY, Rahman M, Suzuki T, Maeta H, Abe Y (2005) Role of NAD(P)H oxidase- and mitochondria-derived reactive oxygen species in cardioprotection of ischemic reperfusion injury by angiotensin II. Hypertension 45(5):860–866

    Article  CAS  PubMed  Google Scholar 

  33. Li Y, Levesque LO, Anand-Srivastava MB (2010) Epidermal growth factor receptor transactivation by endogenous vasoactive peptides contributes to hyperproliferation of vascular smooth muscle cells of SHR. Am J Physiol 299(6):H1959–H1967

    CAS  Google Scholar 

  34. Liang F, Gardner DG (1998) Autocrine/paracrine determinants of strain-activated brain natriuretic peptide gene expression in cultured cardiac myocytes. J Biol Chem 273(23):14612–14619

    Article  CAS  PubMed  Google Scholar 

  35. Lipp P, Huser J, Pott L, Niggli E (1996) Spatially non-uniform Ca2+ signals induced by the reduction of transverse tubules in citrate-loaded guinea-pig ventricular myocytes in culture. J Physiol 497(Pt 3):589–597

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Louch WE, Sheehan KA, Wolska BM (2011) Methods in cardiomyocyte isolation, culture, and gene transfer. J Mol Cell Cardiol 51(3):288–298

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Luers C, Fialka F, Elgner A, Zhu D, Kockskamper J, von Lewinski D, Pieske B (2005) Stretch-dependent modulation of [Na+]i, [Ca2+]i, and pHi in rabbit myocardium—a mechanism for the slow force response. Cardiovasc Res 68(3):454–463

    Article  CAS  PubMed  Google Scholar 

  38. Maejima Y, Kuroda J, Matsushima S, Ago T, Sadoshima J (2011) Regulation of myocardial growth and death by NADPH oxidase. J Mol Cell Cardiol 50(3):408–416

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Maron BJ, Bonow RO, Cannon RO 3rd, Leon MB, Epstein SE (1987) Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy (2). New Engl J Med 316(14):844–852

    Article  CAS  PubMed  Google Scholar 

  40. Maron BJ, Gottdiener JS, Epstein SE (1981) Patterns and significance of distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy. A wide angle, two dimensional echocardiographic study of 125 patients. Am J Cardiol 48(3):418–428

    Article  CAS  PubMed  Google Scholar 

  41. Maron BJ, Sato N, Roberts WC, Edwards JE, Chandra RS (1979) Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum. Comparison of fetuses and infants with and without congenital heart disease and patients with hypertrophic cardiomyopathy. Circulation 60(3):685–696

    Article  CAS  PubMed  Google Scholar 

  42. Maron BJ, Wolfson JK, Epstein SE, Roberts WC (1986) Intramural (“small vessel”) coronary artery disease in hypertrophic cardiomyopathy. J Am Coll Cardiol 8(3):545–557

    Article  CAS  PubMed  Google Scholar 

  43. Nakamura TY, Iwata Y, Arai Y, Komamura K, Wakabayashi S (2008) Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circ Res 103(8):891–899

    Article  CAS  PubMed  Google Scholar 

  44. Ogawa S, Barnett JV, Sen L, Galper JB, Smith TW, Marsh JD (1992) Direct contact between sympathetic neurons and rat cardiac myocytes in vitro increases expression of functional calcium channels. J Clin Invest 89(4):1085–1093

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Ortiz MC, Sanabria E, Manriquez MC, Romero JC, Juncos LA (2001) Role of endothelin and isoprostanes in slow pressor responses to angiotensin II. Hypertension 37(2 Part 2):505–510

    Article  CAS  PubMed  Google Scholar 

  46. Perez NG, de Hurtado MC, Cingolani HE (2001) Reverse mode of the Na+–Ca2+ exchange after myocardial stretch: underlying mechanism of the slow force response. Circ Res 88(4):376–382

    Article  CAS  PubMed  Google Scholar 

  47. Perez NG, Nolly MB, Roldan MC, Villa-Abrille MC, Cingolani E, Portiansky EL, Alvarez BV, Ennis IL, Cingolani HE (2011) Silencing of NHE-1 blunts the slow force response to myocardial stretch. J Appl Physiol 111(3):874–880. doi:10.1152/japplphysiol.01344.2010

    Article  CAS  PubMed  Google Scholar 

  48. Pollack PS, Carson NL, Nuss HB, Marino TA, Houser SR (1991) Mechanical properties of adult feline ventricular myocytes in culture. Am J Physiol 260(1 Pt 2):H234–H241

    CAS  PubMed  Google Scholar 

  49. Rajagopalan S, Laursen JB, Borthayre A, Kurz S, Keiser J, Haleen S, Giaid A, Harrison DG (1997) Role for endothelin-1 in angiotensin II-mediated hypertension. Hypertension 30(1 Pt 1):29–34

    Article  CAS  PubMed  Google Scholar 

  50. Rothstein EC, Byron KL, Reed RE, Fliegel L, Lucchesi PA (2002) H(2)O(2)-induced Ca(2+) overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway. Am J Physiol 283(2):H598–H605

    CAS  Google Scholar 

  51. Sabri A, Byron KL, Samarel AM, Bell J, Lucchesi PA (1998) Hydrogen peroxide activates mitogen-activated protein kinases and Na+–H+ exchange in neonatal rat cardiac myocytes. Circ Res 82(10):1053–1062

    Article  CAS  PubMed  Google Scholar 

  52. Sadoshima J, Xu Y, Slayter HS, Izumo S (1993) Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell 75(5):977–984

    Article  CAS  PubMed  Google Scholar 

  53. Shapiro LM, McKenna WJ (1983) Distribution of left ventricular hypertrophy in hypertrophic cardiomyopathy: a two-dimensional echocardiographic study. J Am Coll Cardiol 2(3):437–444

    Article  CAS  PubMed  Google Scholar 

  54. Shizukuda Y, Buttrick PM (2002) Isoprotrenol activates extracellular signal-regulated protein kinases in cardiomyocytes through calcineurin. Circulation 105(2):E9

    PubMed  Google Scholar 

  55. Snabaitis AK, Hearse DJ, Avkiran M (2002) Regulation of sarcolemmal Na(+)/H(+) exchange by hydrogen peroxide in adult rat ventricular myocytes. Cardiovasc Res 53(2):470–480

    Article  CAS  PubMed  Google Scholar 

  56. Takimoto E, Champion HC, Li M, Ren S, Rodriguez ER, Tavazzi B, Lazzarino G, Paolocci N, Gabrielson KL, Wang Y, Kass DA (2005) Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load. J Clin Invest 115(5):1221–1231

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Tanaka K, Honda M, Takabatake T (2001) Redox regulation of MAPK pathways and cardiac hypertrophy in adult rat cardiac myocyte. J Am Coll Cardiol 37(2):676–685

    Article  CAS  PubMed  Google Scholar 

  58. Thomas WG, Brandenburger Y, Autelitano DJ, Pham T, Qian H, Hannan RD (2002) Adenoviral-directed expression of the type 1A angiotensin receptor promotes cardiomyocyte hypertrophy via transactivation of the epidermal growth factor receptor. Circ Res 90(2):135–142

    Article  CAS  PubMed  Google Scholar 

  59. Villa-Abrille MC, Caldiz CI, Ennis IL, Nolly MB, Casarini MJ, Chiappe de Cingolani GE, Cingolani HE, Perez NG (2010) The Anrep effect requires transactivation of the epidermal growth factor receptor. J Physiol 588(Pt 9):1579–1590

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Villa-Abrille MC, Cingolani HE, Garciarena CD, Ennis IL, Aiello EA (2006) Angiotensin II-induced endothelin-1 release in cardiac myocytes. Medicina 66(3):229–236

    CAS  PubMed  Google Scholar 

  61. Wigle ED, Sasson Z, Henderson MA, Ruddy TD, Fulop J, Rakowski H, Williams WG (1985) Hypertrophic cardiomyopathy. The importance of the site and the extent of hypertrophy: a review. Progr Cardiovasc Dis 28(1):1–83

    Article  CAS  Google Scholar 

  62. Wollert KC, Drexler H (1999) The renin–angiotensin system and experimental heart failure. Cardiovasc Res 43(4):838–849

    Article  CAS  PubMed  Google Scholar 

  63. Xiao L, Pimentel DR, Wang J, Singh K, Colucci WS, Sawyer DB (2002) Role of reactive oxygen species and NAD(P)H oxidase in alpha(1)-adrenoceptor signaling in adult rat cardiac myocytes. Am J Physiol Cell Physiol 282(4):C926–C934

    CAS  PubMed  Google Scholar 

  64. Zhai P, Galeotti J, Liu J, Holle E, Yu X, Wagner T, Sadoshima J (2006) An angiotensin II type 1 receptor mutant lacking epidermal growth factor receptor transactivation does not induce angiotensin II-mediated cardiac hypertrophy. Circ Res 99(5):528–536

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This study was supported in part by grants PIP 1141 from Consejo Nacional de Ciencia y Técnica, Argentina, and PICT 2006–078 from Agencia Nacional de Promoción Científica y Tecnológica, Argentina.

Ethical standards

The authors declare that the experiments fully comply with the current laws of Argentina (the country in which they were performed).

Conflict of interest

None

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to María V. Correa.

Additional information

Correa and Nolly contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Correa, M.V., Nolly, M.B., Caldiz, C.I. et al. Endogenous endothelin 1 mediates angiotensin II-induced hypertrophy in electrically paced cardiac myocytes through EGFR transactivation, reactive oxygen species and NHE-1. Pflugers Arch - Eur J Physiol 466, 1819–1830 (2014). https://doi.org/10.1007/s00424-013-1413-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-013-1413-y

Keywords

Navigation