CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(06): 1047-1057
DOI: 10.1055/a-1711-1055
Atherosclerosis and Ischaemic Disease

Anti-Galectin-2 Antibody Treatment Reduces Atherosclerotic Plaque Size and Alters Macrophage Polarity

Jamie Kane*
1   Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
3   Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Matthijs Jansen*
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
4   Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Sebastian Hendrix
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Laura A. Bosmans
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Linda Beckers
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Claudia van Tiel
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Marion Gijbels
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
5   Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
,
Noam Zelcer
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Carlie J. de Vries
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
6   Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillian's University, Munich, Germany
,
Marc Vervloet
1   Department of Nephrology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Ed Eringa
3   Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Anton J. Horrevoets
7   Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
,
Niels van Royen*
8   Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands
,
Esther Lutgens
2   Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centre, Amsterdam, The Netherlands
6   Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillian's University, Munich, Germany
9   German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
10   Cardiovascular Medicine, Experimental Cardiovascular Immunology Laboratory, Mayo Clinic, Rochester, Minnesota, United States
› Author Affiliations
Funding This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions, grant agreement No. 812699 (to J.K.). We also acknowledge the support from Amsterdam Cardiovascular Sciences for grant support (to M.J.), as well as the Netherlands Cardiovascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research, and Development and the Royal Netherlands Academy of Sciences for the GENIUS-II project ‘Generating the best evidence-based pharmaceutical targets for atherosclerosis’ (CVON2017–22 to E.L.). This study was also supported by the Deutsche Forschungsgemeinschaft (CRC 1123 to E.L., P.v.H.).

Abstract

Background Galectins have numerous cellular functions in immunity and inflammation. Short-term galectin-2 (Gal-2) blockade in ischemia-induced arteriogenesis shifts macrophages to an anti-inflammatory phenotype and improves perfusion. Gal-2 may also affect other macrophage-related cardiovascular diseases.

Objectives This study aims to elucidate the effects of Gal-2 inhibition in atherosclerosis.

MethodsApoE −/− mice were given a high-cholesterol diet (HCD) for 12 weeks. After 6 weeks of HCD, intermediate atherosclerotic plaques were present. To study the effects of anti-Gal-2 nanobody treatment on the progression of existing atherosclerosis, treatment with two llama-derived anti-Gal-2 nanobodies (clones 2H8 and 2C10), or vehicle was given for the remaining 6 weeks.

Results Gal-2 inhibition reduced the progression of existing atherosclerosis. Atherosclerotic plaque area in the aortic root was decreased, especially so in mice treated with 2C10 nanobodies. This clone showed reduced atherosclerosis severity as reflected by a decrease in fibrous cap atheromas in addition to decreases in plaque size.

The number of plaque resident macrophages was unchanged; however, there was a significant increase in the fraction of CD206+ macrophages. 2C10 treatment also increased plaque α-smooth muscle content, and Gal-2 may have a role in modulating the inflammatory status of smooth muscle cells. Remarkably, both treatments reduced serum cholesterol concentrations including reductions in very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein while triglyceride concentrations were unchanged.

Conclusion Prolonged and frequent treatment with anti-Gal-2 nanobodies reduced plaque size, slowed plaque progression, and modified the phenotype of plaque macrophages toward an anti-inflammatory profile. These results hold promise for future macrophage modulating therapeutic interventions that promote arteriogenesis and reduce atherosclerosis.

* Shared authorship.


Supplementary Material



Publication History

Received: 05 November 2020

Accepted: 26 September 2021

Accepted Manuscript online:
01 December 2021

Article published online:
08 February 2022

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