Galectin-3 inhibits cardiac contractility via a tumor necrosis factor alpha-dependent mechanism in cirrhotic rats

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Abstract

Background/Aims

Galectin-3 plays a key pathogenic role in cardiac hypertrophy and heart failure. The present study aimed to investigate the effects of galectin-3 on cardiomyopathy – related factors and cardiac contractility in a rat model of cirrhotic cardiomyopathy.

Methods

Rats were divided into two sets, one for a functional study, the other for cardiac contractile-related protein evaluation. There were four groups in each set: sham operated and sham plus N-acetyllactosamine (N-Lac, a galectin-3 inhibitor; 5 mg/kg); bile duct ligated (BDL) and BDL plus N-Lac. Four weeks after surgery, ventricular level of galectin-3, collagen I and III ratio, tumor necrosis factor alpha (TNFα), and brain natriuretic peptide (BNP) were measured either by Western blots or immunohistochemistry or enzyme-linked immunosorbent assay. Blood pressure was measured by polygraph recorder. Cardiomyocyte contractility was measured by inverted microscopy.

Results

Galectin-3 and collagen I/III ratio were significantly increased in cirrhotic hearts. TNFα and BNP were significantly increased in BDL serum and heart compared with sham controls. Galectin-3 inhibitor significantly decreased galectin-3, TNFα, and BNP in cirrhotic hearts but not in sham controls. N-Lac also significantly improved the blood pressure, and systolic and diastolic cardiomyocyte contractility in cirrhotic rats but had no effect on sham controls.

Conclusion

Increased galectin-3 in the cirrhotic heart significantly inhibited contractility via TNFα. Inhibition of galectin-3 decreased the cardiac content of TNFα and BNP and reversed the decreased blood pressure and depressed contractility in the cirrhotic heart. Galectin-3 appears to play a pathogenic role in cirrhotic cardiomyopathy.

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Most cited references 36

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Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction.

Umesh C Sharma, Saraswati Pokharel, Thomas van Brakel … (2004)

Inflammatory mechanisms have been proposed to be important in heart failure (HF), and cytokines have been implicated to add to the progression of HF. However, it is unclear whether such mechanisms are already activated when hypertrophied hearts still appear well-compensated and whether such early mechanisms contribute to the development of HF. In a comprehensive microarray study, galectin-3 emerged as the most robustly overexpressed gene in failing versus functionally compensated hearts from homozygous transgenic TGRmRen2-27 (Ren-2) rats. Myocardial biopsies obtained at an early stage of hypertrophy before apparent HF showed that expression of galectin-3 was increased specifically in the rats that later rapidly developed HF. Galectin-3 colocalized with activated myocardial macrophages. We found galectin-3-binding sites in rat cardiac fibroblasts and the extracellular matrix. Recombinant galectin-3 induced cardiac fibroblast proliferation, collagen production, and cyclin D1 expression. A 4-week continuous infusion of low-dose galectin-3 into the pericardial sac of healthy Sprague-Dawley rats led to left ventricular dysfunction, with a 3-fold differential increase of collagen I over collagen III. Myocardial galectin-3 expression was increased in aortic stenosis patients with depressed ejection fraction. This study shows that 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. This implies that HF therapy aimed at inflammatory responses may need to be targeted at the early stages of HF and probably needs to antagonize multiple inflammatory mediators, including galectin-3.

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Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis.

Lili Yu, Maxi Meissner, Andries J van Tonder … (2012)

Galectin-3 has been implicated in the development of organ fibrosis. It is unknown whether it is a relevant therapeutic target in cardiac remodeling and heart failure. Galectin-3 knock-out and wild-type mice were subjected to angiotensin II infusion (2.5 µg/kg for 14 days) or transverse aortic constriction for 28 days to provoke cardiac remodeling. The efficacy of the galectin-3 inhibitor N-acetyllactosamine was evaluated in TGR(mREN2)27 (REN2) rats and in wild-type mice with the aim of reversing established cardiac remodeling after transverse aortic constriction. In wild-type mice, angiotensin II and transverse aortic constriction perturbations caused left-ventricular (LV) hypertrophy, decreased fractional shortening, and increased LV end-diastolic pressure and fibrosis (P<0.05 versus control wild type). Galectin-3 knock-out mice also developed LV hypertrophy but without LV dysfunction and fibrosis (P=NS). In REN2 rats, pharmacological inhibition of galectin-3 attenuated LV dysfunction and fibrosis. To elucidate the beneficial effects of galectin-3 inhibition on myocardial fibrogenesis, cultured fibroblasts were treated with galectin-3 in the absence or presence of galectin-3 inhibitor. Inhibition of galectin-3 was associated with a downregulation in collagen production (collagen I and III), collagen processing, cleavage, cross-linking, and deposition. Similar results were observed in REN2 rats. Inhibition of galectin-3 also attenuated the progression of cardiac remodeling in a long-term transverse aortic constriction mouse model. Genetic disruption and pharmacological inhibition of galectin-3 attenuates cardiac fibrosis, LV dysfunction, and subsequent heart failure development. Drugs binding to galectin-3 may be potential therapeutic candidates for the prevention or reversal of heart failure with extensive fibrosis.

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

Adriaan A. Voors, Klaas van Gisbergen, Arenda H. E. A. van Beek … (2009)

Galectins are a family of soluble beta-galactoside-binding lectins that play many important regulatory roles in inflammation, immunity, and cancer. Recently, a role for galectin-3 in the pathophysiology of heart failure (HF) 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. 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 HF.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Mol Hepatol

Journal ID (iso-abbrev): Clin Mol Hepatol

Journal ID (publisher-id): CMH

Title: Clinical and Molecular Hepatology

Publisher: The Korean Association for the Study of the Liver

ISSN (Print): 2287-2728

ISSN (Electronic): 2287-285X

Publication date (Print): April 2022

Publication date (Electronic): 5 January 2022

Volume: 28

Issue: 2

Pages: 232-241

Affiliations

[1 ]Liver Unit, University of Calgary Cumming School of Medicine, Calgary, Canada

[2 ]Department of Internal Medicine, Pusan National University College of Medicine, Yangsan, Korea

[3 ]Department of Hepatology and Infectious Disease, Youan Hospital, Capital Medical University, Beijing, Canada

[4 ]Division of Gastroenterology, Department of Internal Medicine, Uijeongbu Eulji Medical Center, Uijeongbu, Korea

Author notes

Corresponding author : Samuel S. Lee Liver Unit, University of Calgary Cumming School of Medicine, 3330 Hospital Dr NW, Calgary, AB T2N 4N1, Canada Tel: +1 403 220 8457, Fax: +1 403-592-5090 E-mail: samlee@ 123456ucalgary.ca

Editor: Salvatore Piano, University of Padova Faculty of Medicine and Surgery, Italy

[*]

Equal contributors to this study.

Author information

Samuel S. Lee http://orcid.org/0000-0003-4431-272X

Article

Publisher ID: cmh-2021-0141

DOI: 10.3350/cmh.2021.0141

PMC ID: 9013610

PubMed ID: 34986297

SO-VID: 71822f36-68fc-4ab7-876a-49a9ef19745a

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 21 May 2021

Date revision received : 14 December 2021

Date accepted : 4 January 2022

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Galectin-3 inhibits cardiac contractility via a tumor necrosis factor alpha-dependent mechanism in cirrhotic rats

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Karger: Gastroenterology

Most cited references 36

Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction.

Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial fibrogenesis.

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

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