Circulating Gal-3 and sST2 are associated with acute exercise-induced sustained endothelial activation: Possible relevance for fibrosis development?

Abstract

Long-term, intense endurance exercise training can occasionally induce endothelial micro-damage and cardiac fibrosis. The underlying mechanisms are incompletely understood. Twenty healthy, well-trained male participants (10 runners and 10 cyclists) performed a strenuous high-intensity interval training (HIIT) session matched by age, height, weight and maximal oxygen consumption. We assessed the acute exercise response of novel cardiac biomarkers of fibrosis [e.g., galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2)] per exercise modality and their relationship with haemodynamic contributors, such as preload, afterload and cardiac contractility index (CTi), in addition to endothelial damage by sustained activation and shedding of endothelial cells (ECs). Serum Gal-3 and sST2 concentrations were investigated by enzyme-linked immunosorbent assays; haemodynamics were analysed via impedance plethysmography and circulating ECs by flow cytometry. The Gal-3 and sST2 concentrations and ECs were elevated after exercise (P < 0.001), without interaction between exercise modalities. Circulating Gal-3 and sST2 concentrations both showed a positive relationship with ECs (r_rm = 0.68, P = 0.001 and r_rm = 0.57, P = 0.010, respectively, both n = 18). The EC association with Gal-3 was significant only in cyclists, but equally strong for both modalities. Gal-3 was also related to exercise-induced CTi (r_rm = 0.57, P = 0.011, n = 18). Cardiac wall stress is increased after an acute HIIT session but does not differ between exercise modalities. Exercise-released Gal-3 from cardiac macrophages could very probably drive systemic endothelial damage, based on an enhanced CTi. The importance of acute exercise-induced vascular resistances and cardiac contractility for the release of fibrotic biomarkers and any long-term pathological endothelial adaptation should be investigated further, also relative to the exercise modality. NEW FINDINGS: What is the central question of this study? Circulating biomarkers of cardiac wall stress and fibrosis are influenced by physical exercise. The underlying mechanisms per exercise modality are still unclear. What is the main finding and its importance? We show that galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2) are increased after acute exercise but do not differ between running and cycling. One haemodynamic contributor to the secretion of Gal-3 is an enhanced cardiac contractility. Acute exercise-released Gal-3 and sST2 are linked to sustained endothelial activation and cell shedding. This could be relevant in the context of fibrosis development and could identify athletes at risk for pathological endothelial adaptations.

Keywords: early diastolic filling ratio; endothelial cells; galectin-3; high-intensity interval exercise; myocardial contractility index; soluble suppression of tumorigenicity 2.

FIGURE 1

Exemplary flow cytometry gating protocol for the assessment of sustained endothelial activation. After duplet exclusion and extraction of live cells, total mononuclear cells (MNC) were gated for CD31⁺/CD45⁻ endothelial cells (EC). Numbers extracted are given as a percentage of the parent population. CD, cluster of differentiation; FSC‐A, forward scatter ‐area; FSC‐H, forward scatter ‐ height; SSC‐A, side scatter ‐ area, Comp, compensated; FITC, fluorescein isothiocyanate; APC‐Cy7, allophycocyanin cy7 tandem conjugate; AmCya, anemonia majano cyan fluorescent protein.

FIGURE 2

Exercise‐induced novel cardiac biomarkers and sustained endothelial activation. (a, b) Galectin‐3 (Gal‐3; a) and soluble suppression of tumorigenicity 2 (sST2; b) were assessed at baseline and postexercise. Results were significantly increased postexercise, without interaction between groups. Differences in colour indicate the two different exercise modalities, both n = 10. (c) Sustained endothelial activation (EC shedding) was also significantly elevated postexercise, with no interaction for exercise modalities, both n = 9. (d) Circulating Gal‐3 concentrations were significantly related to sustained endothelial activation by circulating endothelial cells (ECs; r _rm = 0.68, P = 0.001, n = 18). Significant differences are indicated by ^*** P < 0.001 and were assessed by mixed ANOVA with one repeated factor (exercise) and one group factor (exercise modality). Squares connected by thick lines indicate mean values of each exercise modality per time point. Parameter association was addressed by repeated‐measures correlation analysis.