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Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction
Umesh C Sharma1, Saraswati Pokharel, Thomas J van Brakel
1Experimental and Molecular Cardiology Laboratory, Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands. y.pinto@carim.unimaas.nl.
Insights
Early increases in galectin-3 signal heart failure risk in hypertrophied hearts. This macrophage-derived mediator drives cardiac fibroblast changes and dysfunction, suggesting early anti-inflammatory therapy is crucial.
Area of Science:
- Cardiovascular Biology
- Inflammation Research
- Molecular Cardiology
Background:
- Inflammatory mechanisms and cytokines are implicated in heart failure (HF) progression.
- It remains unclear if these mechanisms are active in compensated hypertrophied hearts and contribute to HF development.
Purpose of the Study:
- To investigate early inflammatory markers in hypertrophied hearts before the onset of heart failure.
- To determine the role of galectin-3 in the development of cardiac dysfunction.
Main Methods:
- Microarray analysis of rat hearts with varying degrees of hypertrophy and heart failure.
- Immunohistochemical colocalization of galectin-3 with myocardial macrophages.
- In vitro studies using recombinant galectin-3 on cardiac fibroblasts.
- In vivo studies involving galectin-3 infusion in healthy rats.
- Analysis of myocardial galectin-3 expression in human aortic stenosis patients.
Main Results:
- Galectin-3 was the most significantly overexpressed gene in failing versus compensated hearts.
- Increased galectin-3 expression was observed in rats that rapidly developed HF from an early hypertrophic stage.
- Galectin-3 colocalized with activated macrophages and induced cardiac fibroblast proliferation and collagen production.
- Galectin-3 infusion in healthy rats caused left ventricular dysfunction and altered collagen composition.
- Elevated myocardial galectin-3 was found in human patients with aortic stenosis and reduced ejection fraction.
Conclusions:
- Early elevation of galectin-3 expression identifies hearts prone to failure.
- Galectin-3, a macrophage-derived mediator, promotes cardiac fibroblast activity, collagen deposition, and ventricular dysfunction.
- Therapies targeting inflammatory responses in HF may need to focus on early stages and multiple mediators like galectin-3.
Background:
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.
Methods And Results:
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.
Conclusions:
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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