Cellular and Molecular Neurobiology

, Volume 31, Issue 1, pp 17–25 | Cite as

Sympathetic Neurons Express and Secrete MMP-2 and MT1-MMP to Control Nerve Sprouting via Pro-NGF Conversion

  • Erol Saygili
  • Patrick Schauerte
  • Maimouna Pekassa
  • Esra Saygili
  • Gediminas Rackauskas
  • Robert H. G. Schwinger
  • Joachim Weis
  • Christian Weber
  • Nikolaus Marx
  • Obaida R. Rana
Original Research

Abstract

Recently, we have shown that high frequency electrical field stimulation (HFES) of sympathetic neurons (SN) induces nerve sprouting by up-regulation of nerve growth factor (NGF) which targets the tyrosine kinase A receptor (TrkA) in an autocrine/paracrine manner. There is increasing evidence that matrix metalloproteinase-2 (MMP-2) is not only involved in extracellular matrix (ECM) turnover but may also exert beneficial effects during neuronal growth. Therefore, this study aimed to investigate the regulation and function of MMP-2 and its major activator membrane type 1-matrix metalloproteinase (MT1-MMP) as well its inhibitor TIMP-1 in SN under conditions of HFES. Moreover, we analyzed molecular mechanisms of the beneficial effect of losartan, an angiotensin II type I receptor (AT-1)blocker on HFES-induced nerve sprouting. Cell cultures of SN from the superior cervical ganglia (SCG) of neonatal rats were electrically stimulated for 48 h with a frequency of 5 or 50 Hz. HFES increased MMP-2 and MT1-MMP mRNA and protein expression, whereas TIMP-1 expression remained unchanged. Under conditions of HFES, we observed a shift from pro- to active-MMP-2 indicating an increase in MMP-2 enzyme activity. Specific pharmacological MMP-2 inhibition contributed to an increase in pro-NGF amount in the cell culture supernatant and significantly reduced HFES-induced neurite outgrowth. Losartan abolished HFES-induced nerve sprouting in a significant manner by preventing HFES-induced NGF, MMP-2, and MT1-MMP up-regulation. In summary, specific MMP-2 blockade prevents sympathetic nerve sprouting (SNS) by inhibition of pro-NGF conversion while losartan abolishes HFES-induced SNS by reducing total NGF, MMP-2 and MT1-MMP expression.

Keywords

Electrical stimulation Sympathetic neurons Nerve sprouting MMP-2 NGF 

Abbreviations

AF

Atrial fibrillation

ARB

Angiotensin receptor blocker

AT-1

Angiotensin II type I receptor

GAP-43

Growth-associated protein-43

HFES

High frequency electrical field stimulation

MI

Myocardial infarction

MMP-2

Matrix metalloproteinase-2

MT1-MMP

Membrane type 1-matrix metalloproteinase

NGF

Nerve growth factor

RAS

Renin–angiotensin system

SCD

Sudden cardiac death

SCG

Superior cervical ganglia

SN

Sympathetic neurons

SNS

Sympathetic nerve sprouting

TrkA

Tyrosin kinase A receptor

References

  1. Ahmad Z, Milligan CJ, Paton JF, Deuchars J (2003) Angiotensin type 1 receptor immunoreactivity in the thoracic spinal cord. Brain Res 985:21–31CrossRefPubMedGoogle Scholar
  2. Borg TK, Caulfield JB (1981) The collagen matrix of the heart. Fed Proc 40:2037–2041PubMedGoogle Scholar
  3. Cao JM, Chen LS, KenKnight BH, Ohara T, Lee MH, Tsai J, Lai WW, Karagueuzian HS, Wolf PL, Fishbein MC, Chen PS (2000) Nerve sprouting and sudden cardiac death. Circ Res 86:816–821PubMedGoogle Scholar
  4. Chang CM, Wu TJ, Zhou S, Doshi RN, Lee MH, Ohara T, Fishbein MC, Karagueuzian HS, Chen PS, Chen LS (2001) Nerve sprouting and sympathetic hyperinnervation in a canine model of atrial fibrillation produced by prolonged right atrial pacing. Circulation 103:22–25PubMedGoogle Scholar
  5. Deryugina EI, Ratnikov B, Monosov E, Postnova TI, DiScipio R, Smith JW, Strongin AY (2001) MT1-MMP initiates activation of pro-MMP-2 and integrin alphavbeta3 promotes maturation of MMP-2 in breast carcinoma cells. Exp Cell Res 263:209–223CrossRefPubMedGoogle Scholar
  6. Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, Knaut M, Ravens U (2005) The G protein-gated potassium current I(K, ACh) is constitutively active in patients with chronic atrial fibrillation. Circulation 112:3697–3706CrossRefPubMedGoogle Scholar
  7. Fahnestock M, Yu G, Michalski B, Mathew S, Colquhoun A, Ross GM, Coughlin MD (2004) The nerve growth factor precursor proNGF exhibits neurotrophic activity but is less active than mature nerve growth factor. J Neurochem 89:581–592CrossRefPubMedGoogle Scholar
  8. Fogari R, Mugellini A, Destro M, Corradi L, Zoppi A, Fogari E, Rinaldi A (2006) Losartan and prevention of atrial fibrillation recurrence in hypertensive patients. J Cardiovasc Pharmacol 47:46–50CrossRefPubMedGoogle Scholar
  9. Gemein C, Schauerte P, Hatam N, Rana OR, Saygili E, Meyer C, Eickholt C, Schmid M, Knackstedt C, Zarse M, Mischke K (2009) Targeting of cardiac autonomic plexus for modulation of intracardiac neural tone. Europace 11:1090–1096CrossRefPubMedGoogle Scholar
  10. Gould PA, Yii M, McLean C, Finch S, Marshall T, Lambert GW, Kaye DM (2006) Evidence for increased atrial sympathetic innervation in persistent human atrial fibrillation. Pacing Clin Electrophysiol 29:821–829CrossRefPubMedGoogle Scholar
  11. Ju H, Dixon IM (1996) Extracellular matrix and cardiovascular diseases. Can J Cardiol 12:1259–1267PubMedGoogle Scholar
  12. Lee R, Kermani P, Teng KK, Hempstead BL (2001) Regulation of cell survival by secreted proneurotrophins. Science 294:1945–1948CrossRefPubMedGoogle Scholar
  13. Lehmann HC, Köhne A, Bernal F, Jangouk P, Meyer Zu Hörste G, Dehmel T, Hartung HP, Previtali SC, Kieseier BC (2009) Matrix metalloproteinase-2 is involved in myelination of dorsal root ganglia neurons. Glia 57:479–489CrossRefPubMedGoogle Scholar
  14. Leone L, De Stefano ME, Del Signore A, Petrucci TC, Paggi P (2005) Axotomy of sympathetic neurons activates the metalloproteinase-2 enzymatic pathway. Neuropathol Exp Neurol 64:1007–1017CrossRefGoogle Scholar
  15. Liu L, Nattel S (1997) Differing sympathetic and vagal effects on atrial fibrillation in dogs: role of refractoriness heterogeneity. Am J Physiol 273:H805–H816PubMedGoogle Scholar
  16. Madrid AH, Bueno MG, Rebollo JM, Marin I, Pena G, Bernal E, Rodriguez A, Cano L, Cano JM, Cabeza P, Moro C (2002) Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized study. Circulation 106:331–336CrossRefPubMedGoogle Scholar
  17. Meyer C, Rana OR, Saygili E, Gemein C, Becker M, Nolte KW, Weis J, Schimpf T, Knackstedt C, Mischke K, Hoffmann R, Kelm M, Pauza D, Schauerte P (2010) Augmentation of left ventricular contractility by cardiac sympathetic neural stimulation. Circulation 121:1286–1294CrossRefPubMedGoogle Scholar
  18. Milliez P, Messaoudi S, Nehme J, Rodriguez C, Samuel JL, Delcayre C (2009) Beneficial effects of delayed ivabradine treatment on cardiac anatomical and electrical remodeling in rat severe chronic heart failure. Am J Physiol Heart Circ Physiol 296:435–441CrossRefGoogle Scholar
  19. Mischke K, Zarse M, Schmid M, Gemein C, Hatam N, Spillner J, Dohmen G, Rana O, Saygili E, Knackstedt C, Weis J, Pauza D, Bianchi S, Schauerte P (2010) Chronic augmentation of the parasympathetic tone to the atrioventricular node: a nonthoracotomy neurostimulation technique for ventricular rate control during atrial fibrillation. J Cardiovasc Electrophysiol 21:193–199CrossRefPubMedGoogle Scholar
  20. Ould-yahoui A, Tremblay E, Sbai O, Ferhat L, Bernard A, Charrat E, Gueye Y, Lim NH, Brew K, Risso JJ, Dive V, Khrestchatisky M, Rivera S (2009) A new role for TIMP-1 in modulating neurite outgrowth and morphology of cortical neurons. PLoS One 4:e8289CrossRefPubMedGoogle Scholar
  21. Polyakova V, Miyagawa S, Szalay Z, Risteli J, Kostina S (2008) Atrial extracellular matrix remodeling in patients with atrial fibrillation. J Cell Mol Med 12:189–208CrossRefPubMedGoogle Scholar
  22. Rana OR, Zobel C, Saygili E, Brixius K, Gramley F, Schimpf T, Mischke K, Frechen D, Knackstedt C, Schwinger RH, Schauerte P, Saygili E (2008) A simple device to apply equibiaxial strain to cells cultured on flexible membranes. Am J Physiol Heart Circ Physiol 294:532–540CrossRefGoogle Scholar
  23. Rana OR, Saygili E, Meyer C, Gemein C, Krüttgen A, Andrzejewski MG, Ludwig A, Schotten U, Schwinger RH, Weber C, Weis J, Mischke K, Rassaf T, Kelm M, Schauerte P (2009) Regulation of nerve growth factor in the heart: the role of the calcineurin-NFAT pathway. J Mol Cell Cardiol 46:568–578CrossRefPubMedGoogle Scholar
  24. Rana OR, Schauerte P, Hommes D, Schwinger RH, Schröder JW, Hoffmann R, Saygili E (2010a) Mechanical stretch induces nerve sprouting in rat sympathetic neurocytes. Auton Neurosci 155:25–32CrossRefPubMedGoogle Scholar
  25. Rana OR, Schauerte P, Kluttig R, Schröder JW, Koenen R, Weber C, Nolte KW, Weis J, Hoffmann R, Marx N, Saygili E (2010b) Acetylcholine as an age-dependent non-neuronal source in the heart. Auton Neurosci. doi:10.1016/j-autneu.2010.04.011
  26. Saygili E, Rana OR, Saygili E, Reuter H, Frank K, Schwinger RH, Müller-Ehmsen J, Zobel C (2007) Losartan prevents stretch induced electrical remodeling in cultured atrial neonatal myocytes. Am J Physiol Heart Circ Physiol 292:2898–2905CrossRefGoogle Scholar
  27. Saygili E, Rana OR, Meyer C, Gemein C, Andrzejewski MG, Ludwig A, Weber C, Schotten U, Krüttgen A, Weis J, Schwinger RH, Mischke K, Rassaf T, Kelm M, Schauerte P (2009) The angiotensin-calcineurin-NFAT pathway mediates stretch-induced up-regulation of matrix metalloproteinases-2/-9 in atrial myocytes. Basic Res Cardiol 104:435–448CrossRefPubMedGoogle Scholar
  28. Saygili E, Schauerte P, Küppers F, Heck L, Weis J, Weber C, Schwinger RH, Hoffmann R, Schröder JW, Marx N, Rana OR (2010) Electrical stimulation of sympathetic neurons induces autocrine/paracrine effects of NGF mediated by TrkA. J Mol Cell Cardiol 49:79–87CrossRefPubMedGoogle Scholar
  29. Tan AY, Zhou S, Ogawa M, Song J, Chu M, Li H, Fishbein MC, Lin SF, Chen LS, Chen PS (2008) Neural mechanisms of paroxysmal atrial fibrillation and paroxysmal atrial tachycardia in ambulatory canines. Circulation 118:916–925CrossRefPubMedGoogle Scholar
  30. Tang H, Pavel J, Saavedra JM, Brimijoin S (2008) Angiotensin II type 1 receptors may not influence response of spinal autonomic neurons to axonal damage. Neurol Res 30:751–760CrossRefPubMedGoogle Scholar
  31. Voigt N, Maguy A, Yeh YH, Qi X, Ravens U, Dobrev D, Nattel S (2008) Changes in IK, ACh single-channel activity with atrial tachycardia remodelling in canine atrial cardiomyocytes. Cardiovasc Res 77:35–43CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Erol Saygili
    • 1
  • Patrick Schauerte
    • 1
  • Maimouna Pekassa
    • 1
  • Esra Saygili
    • 1
  • Gediminas Rackauskas
    • 1
  • Robert H. G. Schwinger
    • 2
  • Joachim Weis
    • 3
  • Christian Weber
    • 4
  • Nikolaus Marx
    • 1
  • Obaida R. Rana
    • 1
  1. 1.Department of Cardiology, Medical Clinic IRWTH Aachen UniversityAachenGermany
  2. 2.Medical Clinic IIKlinikum WeidenWeidenGermany
  3. 3.Institute for NeuropathologyRWTH Aachen UniversityAachenGermany
  4. 4.Institute for Molecular Cardiovascular ResearchRWTH Aachen UniversityAachenGermany

Personalised recommendations