GALECTIN-3 AS A PHENOTYPICALLY INDICATOR OF CARDIOVASCULAR RISK IN PATIENTS WITH HEART FAILURE

Authors

  • A. E. Berezin Zaporozhye State Medical University,
  • T. A. Samura Zaporozhye State Medical University,

DOI:

https://doi.org/10.14739/2310-1210.2013.6.20822

Keywords:

galectin-3, heart failure, clinical outcomes, diagnostic and prognostic value

Abstract

Chronic heart failure is associated with an activation of the immune system characterized among other factors by the cardiac synthesis and serum expression of proinflammatory cytokines.

Galectin-3 is a 31 kDa member of a growing family of beta-galactoside-binding animal lectins, plays an important role in inflammation, fibrosis, and heart failure.. This protein is expressed in a variety of tissues and cell types and is mainly found in the cytoplasm, although, depending on cell type and proliferative state, a significant amount of this lectin can also be detected in the nucleus, on the cell surface or in the extracellular environment. Galectin-3 is secreted from cells by a novel and incompletely understood mechanism that is independent of the classical secretory pathway through the endoplasmic reticulum/Golgi network. Galectin-3 exhibits pleiotropic biological function, playing a key role in many physiological and pathological processes.

Galectin-3, a beta-galactoside binding protein, contains a C-terminal carbohydrate recognition domain (CRD) and an N-terminal domain that includes several repeats of a proline-tyrosine-glycine-rich motif.

Galectin-3 is expressed abundantly by macrophages, but its function in this cell type is not well understood. Results indicate that galectin-3 contributes to macrophage phagocytosis through an intracellular mechanism. Thus, galectin-3 play an important role in  adaptive immunity by contributing to phagocytic clearance of microorganisms and apoptotic cells.

Galectin-3 expression was low in the cerebrum, heart, and pancreas, and moderate in the liver, ileum, kidney, and adrenal gland. High expression of galectin-3 was found in the lung, spleen, stomach, colon, uterus, and ovary. These findings suggest that galectin-3 is differentially expressed in a variety of organs.

An early increase in galectin-3 expression identifies failure-prone hypertrophied hearts. Galectin-3, a macrophage-derived mediator, induces cardiac fibroblast proliferation, collagen deposition, and ventricular dysfunction.

Galectinl-3 is required for inflammatory and fibrotic responses to aldosteron in vascular smooth muscle cells in vitro and in vivo, suggesting a key role for Gal-3 in vascular fibrosis.

Recently, a role for galectin-3 in the pathophysiology of heart failure has been suggested. Numerous studies have demonstrated the up-regulation of galectin-3 in hypertrophied hearts, its stimulatory effect on macrophage migration, fibroblast proliferation, and the development of fibrosis.

It was investigated the utility of novel serum markers alone or together with natriuretic peptide testing for diagnosis and short-term prognosis estimation in subjects with acute HF. The NT-proBNP was superior to either apelin or galectin-3 for diagnosis of acute HF, although galectin-3 levels were significantly higher in subjects with HF compared with those without. This data shows potential utility of galectin-3 as a useful marker for evaluation of patients with suspected or proven acute HF. Moreover, the combination of galectin-3 with NT-proBNP was the best predictor for prognosis in subjects with acute HF.

A growing body of evidence links macrophage activation and fibrosis to the pathogenesis of heart failure. Galectin-3 is one of the most likely mediators between macrophage activation and myocardial fibrosis. Galectin-3 is significantly correlated with serum markers of cardiac extracellular matrix turnover in of heart failure patients. This implies a relationship between macrophage activation and ECM turnover in patients with HF.

The latter observation is particularly relevant as cardiac remodelling is an important determinant of the clinical outcome of HF and is linked to disease progression and poor prognosis. Because galectin-3 expression is maximal at peak fibrosis and virtually absent after recovery, routine measurement in patients with HF may prove valuable to identify those patients at highest risk for readmission or death, thus enabling physicians to tailor the level of care to individual patient needs. This review summarizes the most recent advances in galectin-3 research, with an emphasis on the role galectin-3 plays in the development and progression of heart failure.

References

Ahmad T. Galectin-3 in heart failure: more answers or more questions? / T. Ahmad, G.M. Felker // J. Am. Heart Assoc. – 2012. – Vol. 1(5). – P. e004374.

Baseline and serial measurements of galectin-3 in patients with heart failure: relationship to prognosis and effect of treatment with valsartan in the Val-HeFT / I.S. Anand, T.S. Rector, M. Kuskowski et al. // Eur. J. Heart Fail. – 2013. –Vol. 15(5). – P. 511–518.

NMR solution studies of hamster galectin-3 and electron microscopic visualization of surface-adsorbed complexes: evidence for interactions between the N-and C-terminal domains / B. Birdsall, J. Feeney, I.D. Burdett et al. // Biochemistry. – 2001. – Vol. 40. – P. 4859–4866.

The cardiac fi broblast: therapeutic target in myocardial remodeling and failure / R.D. Brown, S.K. Ambler, M.D. Mitchell, C.S. Long // Annu. Rev. Pharmacol. Toxicol. – 2005. – Vol. 45. – P. 657–687.

Added value of a physician-and-nurse-directed heart failure clinic: results from the Deventer-Alkmaar heart failure study / P.W.F. Bruggink-Andre de la Porte, D.J.A. Lok, D.J. van Veldhuisen et al. // Heart. – 2007. – Vol. 93. – P. 819–825.

Galectin-3 Mediates Aldosterone-Induced Vascular Fibrosis /

L. Calvier, M. Miana, P. Reboul et al. // Arteriosclerosis, Thrombosis, and Vascular Biology. – 2013. – Vol. 33. – P. 67–75.

Angiotensin II, mitochondria, cytoskeletal, and extracellular

matrix connections: an integrating viewpoint / E.M. Cavanagh,

M. Ferder, F. Inserra, L. Ferder // Am. J. Physiol. Heart Circ.

Physiol. – 2009. – Vol. 296. – P. H550–H558.

Predictive value of plasma galectin-3 in patients with chronic heart failure / K. Chen, R.J. Jiang, C.Q. Wang et al. // Eur. Rev. Med. Pharmacol. Sci. – 2013. – Vol. 17(8). – P.1005–1011.

Biomarkers of heart failure with normal ejection fraction: a systematic review [Електронний ресурс] / J.M. Cheng, K.M. Akkerhuis, L.C. Battes et al. // Eur. J. Heart Fail. – 2013. – Jul 11. – Режим доступу: http://eurjhf.oxfordjournals.org/content/early/2013/07/11/

eurjhf.hft106.abstract.

Coats A.J. Inconsistencies in the development of the ESC

Clinical Practice Guidelines for Heart Failure [Електронний

ресурс] / A.J. Coats, L.G. Shewan // Int. J. Cardiol. – 2013. –

Режим доступу: pii: S0167-5273(13)00954-6. doi: 10.1016/j.

ijcard.2013.05.045.

Cooper D.N. Galectinomics: fi nding themes in complexity /

D.N. Cooper // BiochimBiophysActa. – 2002. – Vol. 1572. –

P. 209–231.

Galectin-3 in heart failure with preserved ejection fraction [Електронний ресурс] / R.A. de Boer, F. Edelmann, A. Cohen-Solal et al. // Eur. J. Heart Fail. – 2013. – May 5. – Режим доступу: http:// www.ncbi.nlm.nih.gov/pubmed/23650131.

Galectin-3: a novel mediator of heart failure development and

progression / R.A. De Boer, A.A. Voors, P. Muntendam et al. //

Eur. J. Heart Fail. – 2009. – Vol. 11. – P. 811–817.

Dumic J. Galectin-3: an open-ended story / J. Dumic, S. Dabelic, M. Flogel // Biochim.Biophys.Acta. – 2006. – Vol. 1760. – P. 616–635.

Galectins: matricellular glycan-binding proteins linking cell adhesion, migration, and survival / M.T. Elola, C. Wolfenstein-Todel, M.F. Troncoso et al. // Cell Mol. Life Sci. – 2007. – Vol. 64. – P. 1679–1700.

Frangogiannis N.G. The immune system and cardiac repair /

N.G. Frangogiannis // Pharmacol. Res. – 2008. – Vol. 58. – P.

–111.

Furtak V. Galectin-3 mediates the endocytosis of beta-1 integrins by breast carcinoma cells / V. Furtak, F. Hatcher, J. Ochieng // Biochem. Biophys. Res. Commun. – 2001. – Vol. 289. – P. 845–850.

American Heart Association Statistics Committee and Stroke

Statistics Subcommittee. Heart disease and stroke statistics-2013 update: a report from the American Heart Association / A.S. Go, D. Mozaffarian, V.L. Roger et al. // Circulation. – 2013. – Vol. 127(1). – P. e6–e245.

Relationship of plasma galectin-3 to renal function in patients with heart failure: effects of clinical status, pathophysiology of heart failure, and presence or absence of heart failure / D.M. Gopal, M. Kommineni, N. Ayalon et al. // J. Am. Heart Assoc. – 2012. – Vol. 1(5). – P. e000760.

Advanced glycation end-products (AGEs) and heart failure: pathophysiology and clinical implications / J.W. Hartog, A.A. Voors, S.J. Bakker et al. // Eur. J. Heart Fail. – 2007. – Vol. 9. – P. 1146–1155.

Hartupee J. Positioning of Inflammatory Biomarkers in the

Heart Failure Landscape [Електронний ресурс] / J. Hartupee,

D.L. Mann // J. Cardiovasc. Transl. Res. – 2013. – May 11. – Режим доступу: http://www.ncbi.nlm.nih.gov/pubmed/23666808.

Galectin-3 regulates myofi broblast activation and hepatic fibrosis / N.C. Henderson, A.C. Mackinnon, S.L. Farnworth et al. // Proc. Natl. Acad. Sci. USA. – 2006. – Vol. 103. – P. 5060–5065.

Galectin-3 expression and secretion links macrophages to the

promotion of renal fibrosis / N.C. Henderson, A.C. Mackinnon,

S.L. Farnworth et al. // Am. J. Pathol. – 2008. – Vol. 172.

– P. 288–298.

Galectin-3/AGE-receptor 3 knockout mice show accelerated

AGE-induced glomerular injury: evidence for a protective role of galectin-3 as an AGE receptor / C. Iacobini, S. Menini, G. Oddi et al. // FASEB J. – 2004. – Vol. 18. – P. 1773–1775.

Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice / C. Iacobini, G. Oddi, S. Menini et al. // Am. J. Physiol. – 2005. – Vol. 289. – P. F611–F621.

Serum galectin-3: a risk factor for vascular complications in type 2 diabetes mellitus / Q.H. Jin, Y.F. Lou, T.L. Li et al. // Chin. Med. J. – 2013. – Vol. 126 (11). – P. 2109–2115.

Expression and immunohistochemical localization of galectin-3

in various mouse tissues / H. Kim, J. Lee, J.W. Hyun et al. // Cell. Biol. Int. – 2007. – 31. – P. 655–662.

Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells / H.R. Kim, H.M. Lin, H. Biliran, A. Raz // Cancer Res. – 1999. – Vol. 59. – P. 4148–4154.

Utility of aminoterminal pro-brain natriuretic peptide, galectin-3, and apelin for the evaluation of patients with acute heart failure / R.R. Kimmenade, J.L.Jr. Januzzi, P.T. Ellinor et al. // J. Am. Coll.Cardiol. – 2006. – Vol. 48. – P. 1217–1224.

Krześlak A. Galectin-3 as a multifunctional protein / A. Krześlak, A. Lipińska // Cell Mol. Biol. Lett. – 2004. – Vol. 9. – P. 305–328.

The relationship between serum galectin-3 and serum markers

of cardiac extracellular matrix turnover in heart failure patients / Y.H. Lin, L.Y. Lin, Y.W. Wu et al. // Clin. Chim. Acta. – 2009. – Vol. 409. – P. 96–99.

N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/ growth-regulatory lectin / Y.H. Liu, M. D’Ambrosio, T.D. Liao et al. // Am. J. Physiol. Heart Circ. Physiol. – 2009. – Vol. 296. – P. H404–H412.

Incremental Prognostic Power of Novel Biomarkers (Growth-

Differentiation Factor-15, High-Sensitivity C-Reactive Protein,

Galectin-3, and High-Sensitivity Troponin-T) in Patients With Advanced Chronic Heart Failure [Електронний ресурс] / D.J. Lok, I.T. Klip, S.I. Lok et al. // Am. J. Cardiol. – 2013. – Jun 29. – Режим доступу: http://www.ncbi.nlm.nih.gov/pubmed/23820571.

Prognostic value of galectin-3, a novel marker of fibrosis, in patients with chronic heart failure: data from the DEAL-HF study / D.J.A. Lok, P. Van Der Meer, P.W.F. Bruggink-Andre de la Porte et al. // Clin. Res. Cardiol. – 2010. – Vol. 99(5). – P. 323–328.

ESC Committee for Practice Guidelines. ESC guidelines for the

diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC / J.J. McMurray, S. Adamopoulos, S.D. Anker et al. // Eur. J. Heart Fail. – 2012. – Vol. 14(8). – P. 803–869.

Plasma biomarkers of myocardial fi brosis and remodeling in terminal heart failure patients supported by mechanical circulatory support devices / H. Milting, P. Ellinghaus, M. Seewald et al. // J. Heart Lung Transplant. – 2008. – Vol. 27. – P. 589–596.

Serial measurement of galectin-3 in patients with chronic heart

failure: results from the ProBNP Outpatient Tailored Chronic

Heart Failure Therapy (PROTECT) study [Електронний ресурс] /S.R. Motiwala, J. Szymonifka, A. Belcher et al. // Eur. J. Heart Fail. – 2013. – May 10. – Режим доступу: http://eurjhf.oxfordjournals.org/content/early/2013/05/09/eurjhf.hft075.abstract.

Characterization of the nuclear import pathways of galectin-3

/ S. Nakahara, N. Oka, Y. Wang et al. // Cancer Res. – 2006. –Vol. 66. – P. 9995–10006.

Role of galectin-3 in human pulmonary fi brosis / Y. Nishi, H. Sano,T. Kawashima et al. // Allergol. Int. – 2007. – Vol. 56. – P. 57–65.

Ochieng J. Extracellular functions of galectin-3 / J. Ochieng,

V. Furtak, P. Lukyanov // Glycoconj J. – 2004. – Vol. 19. – P. 527–535.

N-Acetyl-Ser-Asp-Lys-Pro inhibits phosphorylation of Smad2

in cardiac fi broblasts / S. Pokharel, S. Rasoul, A.J. Roks et al. // Hypertension. – 2002. – Vol. 40. – P. 155–161.

Interferon-gamma induces chronic active myocarditis and cardiomyopathy in transgenic mice / K. Reifenberg, H.A. Lehr, M. Torzewski et al. // Am. J. Pathol. – 2007. – Vol. 171. – P. 463–472.

Critical role of galectin-3 in phagocytosis by macrophages /

H. Sano, D.K. Hsu, J.R. Apgar et al. // J. Clin. Invest. – 2003. – Vol. 112. – P. 389–397.

Thrombospondin-2 is essential for myocardial matrix integrity:

increased expression identifi es failure-prone cardiac hypertrophy / B. Schroen, S. Heymans, U. Sharma et al. // Circ Res. – 2004. – Vol. 95. – P. 515–522.

Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction / U.C. Sharma, S. Pokharel, T.J. Brakel et al. // Circulation. – 2004. – Vol. 110(19). – P. 3121–3128.

Differential associations between renal function and «modifiable» risk factors in patients with chronic heart failure / T.D.J. Smilde, K. Damman, P. Van der Harst et al. // Clin. Res. Cardiol. – 2009.– Vol. 98. – P. 121–129.

Tellez-Sanz R. Human Galectin-3 Selective and High Affi nity Inhibitors. Present State and Future Perspectives [Електронний ресурс] / R. Tellez-Sanz, L. Garcia-Fuentes, A. Vargas-Berenguel // Curr. Med. Chem. – 2013. – Jun 25. – Режим доступу: http://www.

ingentaconnect.com/content/ben/cmc/2013/00000020/00000024/ art00004.

Prognostic value of changes in galectin-3 levels over time in

patients with heart failure: data from CORONA and COACH /

A.R. van der Velde, L. Gullestad, T. Ueland et al. // Circ. Heart

Fail. – 2013. – Vol. 6(2). – P. 219–226.

Vasan R.S. Biomarkers of cardiovascular disease: molecular basis and practical considerations / R.S. Vasan // Circulation. – 2006. – Vol. 113. – P. 2335–2362.

Galectin-3 and cardiac function in survivors of acute myocardial infarction / R.A. Weir, C.J. Petrie, C.A. Murphy et al. // Circ. Heart Fail. – 2013. – Vol. 6 (3). – P. 492–498.

Galectin-3 and the Development of Heart Failure after Acute

Coronary Syndrome: Pilot Experience from PROVE IT-TIMI

/ E. Wilson Grandin, P. Jarolim, S.A. Murphy et al. // Clin.

Chemistry. – 2012. – Vol. 58. – № 1. – P. 267–273.

Wu A.H. Biological variation of galectin-3 and soluble ST2 for

chronic heart failure: implication on interpretation of test results /A.H. Wu, F. Wians, A. Jaffe // Am. Heart J. – 2013. – Vol. 165(6). – P. 995–999.

Yang R.Y. Galectins: structure, function and therapeutic potential/ R.Y. Yang, G.A. Rabinovich, F.T. Liu // Expert. Rev. Mol. Med.– 2008. – Vol. 13. – P. e17–e39.

ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines [Електронний ресурс] / C.W. Yancy, M. Jessup, B. Bozkurt et al. // Circulation. – 2013. – Jun 5.:[in press].

How to Cite

1.
Berezin AE, Samura TA. GALECTIN-3 AS A PHENOTYPICALLY INDICATOR OF CARDIOVASCULAR RISK IN PATIENTS WITH HEART FAILURE. Zaporozhye Medical Journal [Internet]. 2014Jan.29 [cited 2024Oct.16];15(6). Available from: http://zmj.zsmu.edu.ua/article/view/20822