Relationship between Galectin-3 and mineralocorticoid receptor in pulmonary hypertension

Abstract

Background: Galectin-3 (Gal-3), a macrophage receptor, promotes experimental pulmonary arterial hypertension (PAH); however it has not been studied in human PAH. Mineralocorticoid receptor (MR) activates macrophages and has been implicated in PAH.

Objectives: Investigate the relationship between Gal-3 and MR in human and experimental PAH.

Methods: Tufts PAH registry included 109 idiopathic and connective tissue disease-PAH patients (IPAH, CTD-PAH), and 39 controls. Mice with selective MR deletion in myeloid cells were exposed to sugen/hypoxia PH vs. normoxia and compared with controls. A group of PH mice was treated with spironolactone (SP) vs. controls. Lung inflammation was assessed via qPCR and western blot. Gal-3 mRNA and protein were measured in lung tissue and in cultured peritoneal macrophages from myeloid-MR KO mice and controls. Gal-3 levels were measured from human and mouse blood and human and mouse lungs were stained for Gal-3 expression.

Results: PAH patients had elevated plasma Gal-3 levels vs. controls [11.1 (7.8-17) vs. 9.4 (6.6-11.35) ng/ml, median, 25-75%CI] and increased lung staining for Gal-3 positive cells. Serum Gal-3 levels were increased in PH mice and reduced by SP (P<0.01). PH mouse lungs and increased Gal-3 positive cells and this was attenuated in myeloid-MR KO mice (P<0.01). TNF-alpha mRNA was increased in PH lung mice and attenuated in myeloid-MR KOs (P<0.01). In mouse peritoneal macrophages, Gal-3 mRNA and protein expression were attenuated in myeloid-MR KO mice vs. controls (P<0.01).

Conclusion: Gal-3 levels are elevated in human and experimental PAH. In experimental PH, Gal-3 is driven by macrophage MR and both are associated with increased lung inflammation.