Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Journal of Medical Research
Published in: European Journal of Medical Research 1/2013

Open Access 01-12-2013 | Research

GDF-15 protects from macrophage accumulation in a mousemodel of advanced atherosclerosis

Authors: Michael R Preusch, Matthias Baeuerle, Claudia Albrecht, Erwin Blessing, Marc Bischof, Hugo A Katus, Florian Bea

Published in: European Journal of Medical Research | Issue 1/2013

Login to get access

Abstract

Background

The cytokine growth differentiation factor-15 (GDF-15), a member of the TGF beta superfamily, has recently been discovered to play an important role in cardiovascular diseases. It is mostly expressed in macrophages of atherosclerotic lesions, but its impact on advanced atherosclerosis is still unknown. This study was performed to evaluate the effects of GDF-15 in an established mouse model of advanced atherosclerosis.

Methods

Thirty-eight LDL receptor deficient mice received a lethal body radiation. Half of the group was transplanted with bone marrow of GDF-15 deficient mice. Nineteen mice were transplanted with bone marrow from wild-type controls. After 24 weeks on an atherogenic diet, animals were euthanized and sections of the aortic sinus were prepared. Lesion size and lesion composition, as well as macrophage content,were evaluated.

Results

While demonstrating no difference in lesion size, LDL-receptor knockout mice transplanted with bone marrow from GDF-15 deficient mice showed enhanced macrophage accumulation and features of atherosclerotic plaque destabilization, such as thinning of fibrous caps. Immunostaining against intercellular adhesion molecule-1 further revealed an increased expression in mice receiving GDF-15-deficient bone marrow.

Conclusions

This is the first study that demonstrates a protective role of GDF-15 in advanced atherosclerosis and macrophage accumulation, possibly due to the reduced expression of adhesion molecules.
Appendix
Available only for authorised users
Literature
1.
Girn HR, Orsi NM, Homer-Vanniasinkam S: An overview of cytokine interactions in atherosclerosis and implications for peripheral arterial disease. Vasc Med 2007, 12: 299–309.CrossRefPubMed
2.
Robertson AK, Rudling M, Zhou X, Gorelik L, Flavell RA, Hansson GK: Disruption of TGF-beta signalling in T cells accelerates atherosclerosis. J Clin Invest 2003, 112: 1342–1350.PubMedCentralCrossRefPubMed
3.
Topper JN: TGF-beta in the cardiovascular system: molecular mechanisms of a context-specific growth factor. Trends Cardiovasc Med 2000, 10: 132–137.CrossRefPubMed
4.
Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN: MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 1997, 94: 11514–11519.PubMedCentralCrossRefPubMed
5.
Welsh JB, Sapinoso LM, Kern SG, Brown DA, Liu T, Bauskin AR, Ward RL, Hawkins NJ, Quinn DI, Russell PJ, Sutherland RL, Breit SN, Moskaluk CA, Frierson HF Jr, Hampton GM: Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. Proc Natl Acad Sci U S A 2003, 100: 3410–3415.PubMedCentralCrossRefPubMed
6.
Schlittenhardt D, Schober A, Strelau J, Bonaterra GA, Schmiedt W, Unsicker K, Metz J, Kinscherf R: Involvement of growth differentiation factor-15/macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in oxLDL-induced apoptosis of human macrophages in vitro and in arteriosclerotic lesions. Cell Tissue Res 2004, 318: 325–333.CrossRefPubMed
7.
Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, Heineke J, Kotlarz D, Xu J, Molkentin JD, Niessen HW, Drexler H, Wollert KC: The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 2006, 98: 351–360.CrossRefPubMed
8.
Xu J, Kimball TR, Lorenz JN, Brown DA, Bauskin AR, Klevitsky R, Hewett TE, Breit SN, Molkentin JD: GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res 2006, 98: 342–350.CrossRefPubMed
9.
Frank D, Kuhn C, Brors B, Hanselmann C, Lüdde M, Katus HA, Frey N: Gene expression pattern in biomechanically stretched cardiomyocytes: evidence for a stretch-specific gene program. Hypertension 2008, 51: 309–318.CrossRefPubMed
10.
Wollert KC, Kempf T, Peter T, Olofsson S, James S, Johnston N, Lindahl B, Horn-Wichmann R, Brabant G, Simoons ML, Armstrong PW, Califf RM, Drexler H, Wallentin L: Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation 2007, 115: 962–971.CrossRefPubMed
11.
Wollert KC, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, Allhoff T, Peter T, Siegbahn A, Venge P, Drexler H, Wallentin L: Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome. Circulation 2007, 116: 1540–1548.CrossRefPubMed
12.
Kempf T, Björklund E, Olofsson S, Lindahl B, Allhoff T, Peter T, Tongers J, Wollert KC, Wallentin L: Growth-differentiation factor-15 improves risk stratification in ST-segment elevation myocardial infarction. Eur Heart J 2007, 28: 2858–2865.CrossRefPubMed
13.
Kempf T, von Haehling S, Peter T, Allhoff T, Cicoira M, Doehner W, Ponikowski P, Filippatos GS, Rozentryt P, Drexler H, Anker SD, Wollert KC: Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol 2007, 50: 1054–1060.CrossRefPubMed
14.
Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamaté C, Merval R, Fradelizi D, Tedgui A: Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res 2001, 89: 930–934.CrossRefPubMed
15.
Lutgens E, Gijbels M, Smook M, Heeringa P, Gotwals P, Koteliansky VE, Daemen MJ: Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vasc Biol 2002, 22: 975–982.CrossRefPubMed
16.
Ago T, Sadoshima J: GDF15, a cardioprotective TGF-beta superfamily protein. Circ Res 2006, 98: 294–297.CrossRefPubMed
17.
de Jager SC, Bermúdez B, Bot I, Koenen RR, Bot M, Kavelaars A, de Waard V, Heijnen CJ, Muriana FJ, Weber C, van Berkel TJ, Kuiper J, Lee SJ, Abia R, Biessen EA: Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp Med 2011, 208: 217–225.PubMedCentralCrossRefPubMed
18.
Strelau J, Strzelczyk A, Rusu P, Bendner G, Wiese S, Diella F, Altick AL, von Bartheld CS, Klein R, Sendtner M, Unsicker K: Progressive postnatal motoneuron loss in mice lacking GDF-15. J Neurosci 2009, 29: 13640–13648.PubMedCentralCrossRefPubMed
19.
Movat HZ: Demonstration of all connective tissue elements in a single section; pentachrome stains. AMA Arch Pathol 1955, 60: 289–295.PubMed
20.
Puchtler H, Meloan SN: Demonstration of phosphates in calcium deposits: a modification of von Kossa's reaction. Histochemistry 1978, 56: 177–185.CrossRefPubMed
21.
Skipworth RJ, Deans DA, Tan BH, Sangster K, Paterson-Brown DA, Hunter M, Breit SN, Ross JA, Fearon KC: Plasma MIC-1 correlates with systemic inflammation but is not an independent determinant of nutritional status or survival in oesophago-gastric cancer. Br J Cancer 2010, 102: 665–672.PubMedCentralCrossRefPubMed
22.
Reardon CA, Blachowicz L, Lukens J, Nissenbaum M, Getz GS: Genetic background selectively influences innominate artery atherosclerosis: immune system deficiency as a probe. Arterioscler Thromb Vasc Biol 2003, 23: 1449–1454.CrossRefPubMed
23.
Duplàa C, Couffinhal T, Labat L, Moreau C, Petit-Jean ME, Doutre MS, Lamazière JM, Bonnet J: Monocyte/macrophage recruitment and expression of endothelial adhesion proteins in human atherosclerotic lesions. Atherosclerosis 1996, 121: 253–266.CrossRefPubMed
24.
Davies MJ, Gordon JL, Gearing AJ, Pigott R, Woolf N, Katz D, Kyriakopoulos A: The expression of the adhesion molecules ICAM-1, VCAM-1, PECAM, and E-selectin in human atherosclerosis. J Pathol 1993, 171: 223–229.CrossRefPubMed
25.
Yang PY, Rui YC: Intercellular adhesion molecule-1 and vascular endothelial growth factor expression kinetics in macrophage-derived foam cells. Life Sci 2003, 74: 471–480.CrossRefPubMed
26.
Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R: Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997, 336: 1276–1282.CrossRefPubMed
27.
Loree HM, Tobias BJ, Gibson LJ, Kamm RD, Small DM, Lee RT: Mechanical properties of model atherosclerotic lesion lipid pools. Arterioscler Thromb 1994, 14: 230–234.CrossRefPubMed
28.
Sukhova GK, Schönbeck U, Rabkin E, Schoen FJ, Poole AR, Billinghurst RC, Libby P: Evidence for increased collagenolysis by interstitial collagenases-1 and −3 in vulnerable human atheromatous plaques. Circulation 1999, 99: 2503.CrossRefPubMed
29.
Jackson CL, Bennett MR, Biessen EA, Johnson JL, Krams R: Assessment of unstable atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2007, 27: 714–720.CrossRefPubMed
30.
Sjöland H, Eitzman DT, Gordon D, Westrick R, Nabel EG, Ginsburg D: Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2000, 20: 846–852.CrossRefPubMed
31.
32.
Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW, Bauskin AR, Wu L, Pankhurst G, Jiang L, Junankar S, Hunter M, Fairlie WD, Lee NJ, Enriquez RF, Baldock PA, Corey E, Apple FS, Murakami MM, Lin EJ, Wang C, During MJ, Sainsbury A, Herzog H, Breit SN: Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med 2007, 13: 1333–1340.CrossRefPubMed
Metadata
Title
GDF-15 protects from macrophage accumulation in a mousemodel of advanced atherosclerosis
Authors
Michael R Preusch
Matthias Baeuerle
Claudia Albrecht
Erwin Blessing
Marc Bischof
Hugo A Katus
Florian Bea
Publication date
01-12-2013
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2013
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/2047-783X-18-19

Other articles of this Issue 1/2013

European Journal of Medical Research 1/2013 Go to the issue

Research

RETRACTED ARTICLE: Systematic study of cilostazol on secondary stroke prevention: a meta-analysis

Research

RETRACTED ARTICLE: Establishing an osteosarcoma associated protein-protein interaction network to explore the pathogenesis of osteosarcoma

Research

The therapeutic efficacy of I131-PSCA-mAb in orthotopic mouse models of prostate cancer

Research

Improvements of surgical techniques in a rat model of an orthotopic single lung transplant

Research

Level of information about the relationship between diabetes mellitus and periodontitis - results from a nationwide diabetes information program

Case report

Comorbidities in combined retinal artery and vein occlusions