Galectin-3 gene deletion alters lipid profile in healthy and cardiomyopathy mouse hearts

Abstract

Galectin-3 (Gal3) is known to interact with glycans of proteins and lipids. In cardiovascular disease, the elevated expression of Gal3 mediates inflammation, hypertrophy and fibrosis. We explored the effect of Gal3 on the cardiac lipid profile in healthy mice or in mice with dilated cardiomyopathy (DCM). Using lipidomics and gene-targeted mouse models, we studied the influence of Gal3 gene deletion on cardiac lipid profiles in the healthy mice or mice with DCM. Cardiac-restricted transgenic activation of Hippo pathway led to DCM phenotype and Gal3 upregulation. DCM mice were cross-bred with Gal3 gene knockout (KO) mice to obtain genotypes of non-transgenic (nTG), Gal3-KO, DCM and DCM/KO. Alterations in the lipid classes and species due to Gal3-KO were identified by lipidomics in hearts from mice of four genotypes. In the nTG background, Gal3-KO increased ether lipids and lysophospholipids, and induced diverse changes of sphingolipid subclasses. The DCM hearts exhibited profound lipidomic changes including increase in sphingolipids and reduction in ether lipids and triglycerides, which were partially reversed by Gal3 deletion. We demonstrated the nuclear and mitochondrial localization of Gal-3 in DCM hearts. Transcriptomics revealed that Gal3 deletion in the DCM background partially restored the suppressed expression of mitochondrial lipid metabolic genes. In conclusion, we report multiple alterations in the lipid classes and species in the heart by Gal3 deletion in the healthy mice and, more importantly mice with DCM background. Our findings suggest that Gal3 alters cardiac contents of lipids in the DCM model in part through suppression of mitochondrial metabolism.