Skip to main content

Advertisement

SpringerLink
Log in

Transcription factor PEX1 modulates extracellular matrix turnover through regulation of MMP-9 expression

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

The phenylephrine-induced complex-1 (PEX1) transcription factor, also known as zinc-finger protein 260 (Zfp260), is an effector of endothelin-1 and α1-adrenergic signaling in cardiac hypertrophy. However, the role of PEX1 in transcriptional regulation of myocardial remodeling remains largely unknown. In the present study, we used PEX1 gain- and loss-of-function to examine the effects of PEX1 on left ventricular remodeling. Adenoviral constructs expressing PEX1, antisense PEX1, or LacZ were delivered by local injection into the anterior wall of the left ventricle in Sprague–Dawley rats. PEX1 overexpression led to induction of hypertrophic gene program and increased fibrosis. In agreement with this, the expression of genes involved in the fibrotic process, such as collagens I and III, matrix metalloproteinases (MMPs), fibronectin-1, transforming growth factor beta-1 and connective tissue growth factor, were significantly up-regulated following PEX1 overexpression, whereas silencing of PEX1 significantly inhibited the expression of pro-fibrotic genes and increased left ventricular ejection fraction and fractional shortening. In vitro luciferase reporter assays showed that PEX1 regulates the expression of MMP-9 by activating promoter. Furthermore, PEX1 gain- and loss-of-function experiments in rat neonatal cardiac fibroblasts and myocytes revealed that MMP-9 gene expression was affected by PEX1 predominantly in fibroblasts. Our results indicate that PEX1 is involved in regulating cardiac fibrosis and extracellular matrix turnover, particularly fibroblasts being responsible for the fibrosis-associated changes in gene expression. Furthermore, PEX1 activation of the MMP-9 promoter triggers the pro-fibrotic response directed by PEX1.

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
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Abreu JG, Ketpura NI, Reversade B, De Robertis EM (2002) Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-beta. Nat Cell Biol 4:599–604

    CAS  PubMed  PubMed Central  Google Scholar 

  • Braunwald E (2013) Heart failure. JACC Heart Fail 1:1–20

    Article  PubMed  Google Scholar 

  • Bujak M, Frangogiannis NG (2007) The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74:184–195

    Article  CAS  PubMed  Google Scholar 

  • Chan W, Duffy SJ, White DA, Gao X-M, Du X-J, Ellims AH, Dart AM, Taylor AJ (2012) Acute left ventricular remodeling following myocardial infarction: coupling of regional healing with remote extracellular matrix expansion. JACC Cardiovasc Imaging 5:884–893

    Article  PubMed  Google Scholar 

  • Chen MM, Lam A, Abraham JA, Schreiner GF, Joly AH (2000) CTGF expression is induced by TGF-B in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis. J Mol Cell Cardiol 32:1805–1819

  • Chien KR (1999) Stress pathways and heart failure. Cell 98:555–558

    Article  CAS  PubMed  Google Scholar 

  • Cleutjens JP, Verluyten MJ, Smiths JF, Daemen MJ (1995) Collagen remodeling after myocardial infarction in the rat heart. Am J Pathol 147:325–338

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dayer C, Stamenkovic I (2015) Recruitment of matrix metalloproteinase-9 (MMP-9) to the fibroblast cell surface by lysyl hydroxylase 3 (LH3) triggers transforming growth factor-β (TGF-β) activation and fibroblast differentiation. J Biol Chem 290:13763–13778

  • Debrus S, Rahbani L, Marttila M, Delorme B, Paradis P, Nemer M (2005) The zinc finger-only protein Zfp260 is a novel cardiac regulator and a nuclear effector of α1-adrenergic signaling. Mol Cell Biol 25:8669–8682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dobaczewski M, Gonzalez-Quesada C, Frangogiannis NG (2010) The extracellular matrix as a modulator of the inflammatory and reparative response following myocardial infarction. J Mol Cell Cardiol 48:504–511

    Article  CAS  PubMed  Google Scholar 

  • Eberhardt W, Akool E-S, Rebhan J, Frank S, Beck K-F, Franzen R, Hamada FMA, Pfeilschifter J (2002) Inhibition of cytokine-induced matrix metalloproteinase 9 expression by peroxisome proliferator-activated receptor alpha agonists is indirect and due to a NO-mediated reduction of mRNA stability. J Biol Chem 277:33518–33528

    Article  CAS  PubMed  Google Scholar 

  • Fan D, Takawale A, Lee J, Kassiri Z (2012) Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5:15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frangogiannis N (2000) Myofibroblasts in reperfused myocardial infarcts express the embryonic form of smooth muscle myosin heavy chain (SMemb). Cardiovasc Res 48:89–100

    Article  CAS  PubMed  Google Scholar 

  • Garrett Q, Khaw PT, Blalock TD, Schultz GS, Grotendorst GR, Daniels JT (2004) Involvement of CTGF in TGF-β1–stimulation of myofibroblast differentiation and collagen matrix contraction in the presence of mechanical stress. Investig Opthalmology Vis Sci 45:1109–1116

  • Gullestad L, Ueland T, Vinge LE, Finsen A, Yndestad A, Aukrust P (2012) Inflammatory cytokines in heart failure: mediators and markers. Cardiology 122:23–35

    Article  CAS  PubMed  Google Scholar 

  • Ikonomidis JS, Hendrick JW, Parkhurst AM, Herron AR, Escobar PG, Dowdy KB, Stroud RE, Hapke E, Zile MR, Spinale FG (2005) Accelerated LV remodeling after myocardial infarction in TIMP-1-deficient mice: effects of exogenous MMP inhibition. Am J Physiol Heart Circ Physiol 288:H149–H158

    Article  CAS  PubMed  Google Scholar 

  • Jessup M, Brozena S (2003) Heart Failure. N Engl J Med 348:2007–2018

    Article  PubMed  Google Scholar 

  • Komati H, Maharsy W, Beauregard J, Hayek S, Nemer M (2011) ZFP260 is an inducer of cardiac hypertrophy and a nuclear mediator of endothelin-1 signaling. J Biol Chem 286:1508–1516

    Article  CAS  PubMed  Google Scholar 

  • Krishnamurthy P, Peterson JT, Subramanian V, Singh M, Singh K (2009) Inhibition of matrix metalloproteinases improves left ventricular function in mice lacking osteopontin after myocardial infarction. Mol Cell Biochem 322:53–62

    Article  CAS  PubMed  Google Scholar 

  • Lalit PA, Salick MR, Nelson DO, Squirrell JM, Shafer CM, Patel NG, Saeed I, Schmuck EG, Markandeya YS, Wong R, Lea MR, Eliceiri KW, Hacker TA, Crone WC, Kyba M, Garry DJ, Stewart R, Thomson JA, Downs KM, Lyons GE, Kamp TJ (2016) Lineage reprogramming of fibroblasts into proliferative induced cardiac progenitor cells by defined factors. Cell Stem Cell 18:354–367

  • Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18:816–827

    Article  CAS  PubMed  Google Scholar 

  • Lindner D, Zietsch C, Tank J, Sossalla S, Fluschnik N, Hinrichs S, Maier L, Poller W, Blankenberg S, Schultheiss H-P, Tschöpe C, Westermann D (2014) Cardiac fibroblasts support cardiac inflammation in heart failure. Basic Res Cardiol 109:428

    Article  PubMed  Google Scholar 

  • Ma F, Li Y, Jia L, Han Y, Cheng J, Li H, Qi Y, Du J (2012) Macrophage-stimulated cardiac fibroblast production of IL-6 is essential for TGF β/Smad activation and cardiac fibrosis induced by angiotensin II. PLoS ONE 7:e35144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma Y, de Castro Brás LE, Toba H, Iyer RP, Hall ME, Winniford MD, Lange RA, Tyagi SC, Lindsey ML (2014) Myofibroblasts and the extracellular matrix network in post-myocardial infarction cardiac remodeling. Pflugers Arch 466:1113–1127

    CAS  PubMed  PubMed Central  Google Scholar 

  • McMurray JJ, Pfeffer MA (2005) Heart failure. Lancet 365:1877–1889

    Article  PubMed  Google Scholar 

  • Meléndez GC, McLarty JL, Levick SP, Du Y, Janicki JS, Brower GL (2010) Interleukin 6 mediates myocardial fibrosis, concentric hypertrophy, and diastolic dysfunction in rats. Hypertension 56:225–231

    Article  PubMed  PubMed Central  Google Scholar 

  • Moilanen AM, Rysä J, Mustonen E, Serpi R, Aro J, Tokola H, Leskinen H, Manninen A, Levijoki J, Vuolteenaho O, Ruskoaho H (2011) Intramyocardial BNP gene delivery improves cardiac function through distinct context-dependent mechanisms. Circ Heart Fail 4:483–495

    Article  CAS  PubMed  Google Scholar 

  • Oka T, Xu J, Molkentin JD (2007) Re-employment of developmental transcription factors in adult heart disease. Semin Cell Dev Biol 18:117–131

    Article  CAS  PubMed  Google Scholar 

  • Pikkarainen S, Tokola H, Majalahti-Palviainen T, Kerkela R, Hautala N, Bhalla SS, Charron F, Nemer M, Vuolteenaho O, Ruskoaho H (2003) GATA-4 is a nuclear mediator of mechanical stretch-activated hypertrophic program. J Biol Chem 278:23807–23816

    Article  CAS  PubMed  Google Scholar 

  • Pikkarainen S, Tokola H, Kerkelä R, Ruskoaho H (2004) GATA transcription factors in the developing and adult heart. Cardiovasc Res 63:196–207

    Article  CAS  PubMed  Google Scholar 

  • Romanic AM, Burns-Kurtis CL, Gout B, Berrebi-Bertrand I, Ohlstein EH (2001) Matrix metalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit. Life Sci 68:799–814

    Article  CAS  PubMed  Google Scholar 

  • Rysä J, Tenhunen O, Serpi R, Soini Y, Nemer M, Leskinen H, Ruskoaho H (2010) GATA-4 is an angiogenic survival factor of the infarcted heart. Circ Heart Fail 3:440–450

    Article  PubMed  Google Scholar 

  • Sano M, Fukuda K, Kodama H, Pan J, Saito M, Matsuzaki J, Takahashi T, Makino S, Kato T, Ogawa S (2000) Interleukin-6 family of cytokines mediate angiotensin II-induced cardiac hypertrophy in rodent cardiomyocytes. J Biol Chem 275:29717–29723

    Article  CAS  PubMed  Google Scholar 

  • Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, Gabbiani G (1998) The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-β1. J Cell Biol 142:873–881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Serpi R, Tolonen A-M, Huusko J, Rysä J, Tenhunen O, Ylä-Herttuala S, Ruskoaho H (2011) Vascular endothelial growth factor-B gene transfer prevents angiotensin II-induced diastolic dysfunction via proliferation and capillary dilatation in rats. Cardiovasc Res 89:204–213

    Article  CAS  PubMed  Google Scholar 

  • Shinde AV, Frangogiannis NG (2014) Fibroblasts in myocardial infarction: a role in inflammation and repair. J Mol Cell Cardiol 70:74–82

    Article  CAS  PubMed  Google Scholar 

  • Sun Y (2000) Infarct scar: a dynamic tissue. Cardiovasc Res 46:250–256

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, Zhang JQ, Zhang JQ, Lamparter S (2000) Cardiac remodeling by fibrous tissue after infarction in rats. J Lab Clin Med 135:316–323

    Article  CAS  PubMed  Google Scholar 

  • Suo M, Hautala N, Foldes G, Szokodi I, Toth M, Leskinen H, Uusimaa P, Vuolteenaho O, Nemer M, Ruskoaho H (2002) Posttranscriptional control of BNP gene expression in angiotensin II-induced hypertension. Hypertension 39:803–808

  • Takai S, Jin D, Inagaki S, Yamamoto D, Tanaka K, Miyazaki M (2007) Significance of matrix metalloproteinase-9 in cardiac dysfunction during the very acute phase after myocardial infarction in hamsters. Eur J Pharmacol 572:57–60

    Article  CAS  PubMed  Google Scholar 

  • Talman V, Ruskoaho H (2016) Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration. Cell Tissue Res 365:563–581

  • Tenhunen O, Rysä J, Ilves M, Soini Y, Ruskoaho H, Leskinen H (2006a) Identification of cell cycle regulatory and inflammatory genes as predominant targets of p38 mitogen-activated protein kinase in the heart. Circ Res 99:485–493

    Article  CAS  PubMed  Google Scholar 

  • Tenhunen O, Soini Y, Ilves M, Rysä J, Tuukkanen J, Serpi R, Pennanen H, Ruskoaho H, Leskinen H (2006b) p38 Kinase rescues failing myocardium after myocardial infarction: evidence for angiogenic and anti-apoptotic mechanisms. FASEB J 20:1907–1909

    Article  CAS  PubMed  Google Scholar 

  • Turner NA (2015) Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs). J Mol Cell Cardiol 94:189–200

    Article  PubMed  Google Scholar 

  • van Nieuwenhoven FA, Turner NA (2013) The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction. Vasc Pharmacol 58:182–188

    Article  Google Scholar 

  • Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML (2013) Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology (Bethesda) 28:391–403

    CAS  Google Scholar 

  • Yu Q, Stamenkovic I (2000) Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev 14:163–176

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Professor Wolfgang Eberhardt (Pharmazentrum Frankfurt/ZAFES, Klinikum der Goethe-Universität Frankfurt, Frankfurt am Main, Germany) for the pGL-III-pMMP9-Luc construct and Professor Olli Vuolteenaho (Research Unit of Biomedicine, University of Oulu, Finland) for kindly providing Ang II. We also thank Marja Arbelius, Kati Lampinen, Kirsi Salo and Sirpa Rutanen for their expert technical assistance. This work was supported by the Finnish Foundation for Cardiovascular Research (to A.J.A., H.R., Z.S.), the Sigrid Jusélius Foundation (to H.R.), the Academy of Finland (grants. 266661 to H.R. and 276747 to J.R.) and the Heart and Stroke Foundation of Canada (grant. NA7301 to H.K. and M.N.).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Research Unit of Biomedicine, Faculty of Medicine, University of Oulu, POB 5000, 90014, Oulu, Finland

    Alicia Jurado Acosta, Zoltan Szabo & Heikki Ruskoaho

  2. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211, Kuopio, Finland

    Jaana Rysä

  3. Cancer and Translational Medicine Research Unit, University of Oulu, POB 5000, 90014, Oulu, Finland

    Anne-Mari Moilanen

  4. Oulu University Hospital and Medical Research Center Oulu, POB 5000, 90014, Oulu, Finland

    Anne-Mari Moilanen

  5. Molecular Genetics and Cardiac Regeneration Laboratory, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, K1H8M5, Ontario, Canada

    Hiba Komati & Mona Nemer

  6. Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, POB 56, 00014, Helsinki, Finland

    Heikki Ruskoaho

Authors
  1. Alicia Jurado Acosta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaana Rysä
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zoltan Szabo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anne-Mari Moilanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiba Komati
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mona Nemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Heikki Ruskoaho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heikki Ruskoaho.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 1786 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jurado Acosta, A., Rysä, J., Szabo, Z. et al. Transcription factor PEX1 modulates extracellular matrix turnover through regulation of MMP-9 expression. Cell Tissue Res 367, 369–385 (2017). https://doi.org/10.1007/s00441-016-2527-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-016-2527-2

Keywords

Search

Navigation