Myocardial Galectin-3 Expression Is Associated with Remodeling of the Pressure-Overloaded Heart and May Delay the Hypertrophic Response without Affecting Survival, Dysfunction, and Cardiac Fibrosis

Abstract

The b-galactosideebinding animal lectin galectin-3 is predominantly expressed by activated macrophages and is a promising biomarker for patients with heart failure. Galectin-3 regulates inflammatory and fibrotic responses; however, its role in cardiac remodeling remains unclear. We hypothesized that galectin-3 may be up-regulated in the pressure-overloaded myocardium and regulate hypertrophy and fibrosis. In normal mouse myocardium, galectin-3 was constitutively expressed in macrophages and was localized in atrial but not ventricular cardiomyocytes. In a mouse model of transverse aortic constriction, galectin-3 expression was markedly up-regulated in the pressure-overloaded myocardium. Early up-regulation of galectin-3 was localized in subpopulations of macrophages and myofibroblasts; however, after 7 to 28 days of transverse aortic constriction, a subset of cardiomyocytes in fibrotic areas contained large amounts of galectin-3. In vitro, cytokine stimulation suppressed galectin-3 synthesis by macrophages and cardiac fibroblasts. Correlation studies revealed that cardiomyocytebut not macrophage-specific galectin-3 localization was associated with adverse remodeling and dysfunction. Galectin-3 knockout mice exhibited accelerated cardiac hypertrophy after 7 days of pressure overload, whereas female galectin-3 knockouts had delayed dilation after 28 days of transverse aortic constriction. However, galectin-3 loss did not affect survival, systolic and diastolic dysfunction, cardiac fibrosis, and cardiomyocyte hypertrophy in the pressure-overloaded heart. Despite its potential role as a prognostic biomarker, galectin-3 is not a critical modulator of cardiac fibrosis but may delay the hypertrophic response. (Am J Pathol 2016, 186: 1114e1127; http://dx

Plasma and Cardiac Galectin-3 in Patients With Heart Failure Reflects Both Inflammation and Fibrosis

“…A recent study, however, suggested that macrophages are not the only source of Gal-3 in the myocardium in a mouse model of transverse aortic constriction. 31 Early upregulation of Gal-3 after pressure overload was localized in subpopulations of macrophages and myofibroblasts. Of note, after 1 to 4 weeks of transverse aortic constriction, a subset of cardiomyocytes in fibrotic areas contained large amounts of Gal-3.…”

“…Of note, after 1 to 4 weeks of transverse aortic constriction, a subset of cardiomyocytes in fibrotic areas contained large amounts of Gal-3. 31 Further studies are needed to clarify whether inflammatory cells are indeed the source of myocardial Gal-3 in iCMP and which type of cell is responsible for it.…”

The differences in the relationship between diastolic dysfunction, selected biomarkers and collagen turn-over in heart failure patients with preserved and reduced ejection fraction

“…However, recent studies have shown that GAL-3 is not a critical modulator of cardiac fibrosis but may delay the hypertrophic response and further studies are needed to clearly establish its role [36]. Interestingly, in patients with HFpEF, there was a statistically significant correlation between adiponectin and MMP-2 with the E/E' and an inverse correlation of PIIINP with E/A.…”

Activation of TGF-β1/α-SMA/Col I Profibrotic Pathway in Fibroblasts by Galectin-3 Contributes to Atrial Fibrosis in Experimental Models and Patients

“…Gal-3 is expressed predominantly by fibroblasts and macrophages in the majority of previous studies [20][21][22]. However, some also reported that Gal-3 is expressed in ventricular myocytes in a pressure-overloaded remodeling heart model and that a high density of Gal-3-positive myocytes is related to abnormalities in remodeling and heart function [23]. Furthermore, HL-1 cells have been demonstrated to express Gal-3 at baseline and remarkably induce its expression following protein kinase C activation, indicating that cardiomyocytes may also act as a source of Gal-3 in the heart [24] and possibly be greatly induced in pathological conditions.…”

“…Consistent with this result, we found that the TGF-β1/α-SMA/Col I pathway was induced in neonatal rat cardiac fibroblasts by Gal-3-enriched conditioned HL-1 culture media, and further confirmed the role of Gal-3 in fibroblast differentiation and proliferation with recombinant human Gal-3 protein treatment, both at 10 and 30 μg/mL; exogenous Gal-3 activated the profibrotic pathway and induced fibroblast proliferation, as detected by CCK-8. All of these results led us to the conclusion that although cardiomyocytes barely express Gal-3 under physiological conditions [9], under pathological conditions, cardiomyocytes may also act as an alternative source of Gal-3 [23,24], inducing fibroblasts to synthesize collagen and other pro-fibrotic components of the extracellular matrix.…”