Galectin-3 mediates cardiac remodeling caused by impaired glucose and lipid metabolism through inhibiting two pathways of activating Akt

Abstract

Pathological cardiac remodeling is a leading cause of mortality in patients with diabetes. Given the glucose and lipid metabolism disorders (GLDs) in patients with diabetes, it is urgent to conduct a comprehensive study of the myocardial damage under GLDs and find key mechanisms. Apolipoprotein E knockout (ApoE^-/-) mice, low-density lipoprotein receptor heterozygote (Ldlr^+/-) Syrian golden hamsters, or H9C2 cells were used to construct GLDs models. GLDs significantly promoted cardiomyocyte fibrosis, apoptosis, and hypertrophy in vivo and in vitro, but inhibition of galectin-3 (Gal-3) could significantly reverse this process. Then, the signal transmission pathways were determined. It was found that GLDs considerably inhibited the phosphorylation of Akt at Thr³⁰⁸/Ser⁴⁷³, whereas the silencing of Gal-3 could reverse the inhibition of Akt activity through phosphoinositide 3-kinase-Akt^Thr308 (PI3K-Akt^Thr308) and AMP-activated protein kinase-mammalian target of rapamycin complex 2-Akt^Ser473 (AMPK-mTOR2-Akt^Ser473) pathways. Finally, the PI3K, mTOR, AMPK inhibitor, and Akt activator were used to investigate the role of pathways in regulating cardiac remodeling. Phospho-Akt^Thr308 could mediate myocardial fibrosis, whereas myocardial apoptosis and hypertrophy were regulated by both phospho-Akt^Thr308 and phospho-Akt^Ser473. In conclusion, Gal-3 was an important regulatory factor in GLDs-induced cardiac remodeling, and Gal-3 could suppress the phosphorylation of Akt at different sites in mediating cardiomyocyte fibrosis, apoptosis, and hypertrophy.NEW & NOTEWORTHY Studies on the pathogenesis of diabetic cardiac remodeling are highly desired. Glucose and lipid metabolism are both disordered in diabetes. Glucose and lipid metabolism disturbances promote myocardial fibrosis, apoptosis, and hypertrophy through galectin-3. Galectin-3 promotes cardiac remodeling by inhibiting phosphorylation of Akt^Thr308 or Akt^Ser473. The present study finds that glucose and lipid metabolism disorders are important causes for myocardial damage and provides novel ideas for the prevention and treatment of diabetic cardiac remodeling.

Keywords: Akt; cardiac remodeling; diabetes; galectin-3; phosphorylation.