Abstract 14872: Lactate Promotes Endothelial-to-Mesenchymal Transition via Snail1 Lactylation After Myocardial Infarction

Abstract

Introduction: High levels of lactate are positively associated with the prognosis and mortality in the patients with acute heart attack and heart failure. Endothelial-to-mesenchymal transition (EndMT) plays an important role in the progression of cardiac fibrosis in multiple cardiovascular diseases. We investigated whether lactate exerts a biological role in EndMT following myocardial infarction (MI). Methods: MI was induced in endothelial cell specific GFP labeled (TIE2GFP) mice by left anterior descending (LAD) coronary artery ligation. To suppress lactate production, 2-Deoxy-D-glucose (2-DG, 2g/kg body weight) was intraperitoneally injected daily for 7 days. Supplemental lactic acid (adjust to pH 6.8, 0.5 g/kg body weight) was administrated to mice either by i.p. injection every 7 days for 1 or 4 weeks or using osmotic mini-pumps after surgery. In vitro , endothelial cells were treated with 5 mM or 10 mM L-lactic acid followed by normoxic or hypoxic challenge in a hypoxia chamber. Results: Our data showed that inhibition of lactate production by 2-DG ameliorated MI induced EndMT, cardiac fibrosis and cardiac dysfunction. On the contrary, administration of supplemental lactate further promoted EndMT and worsened cardiac dysfunction post-MI. In vitro analysis shows that treatment of endothelial cells with lactate decreases the expression of endothelial cell markers and accelerates mesenchymal marker expression, as well as disrupts endothelial cell function and induces mesenchymal like function following hypoxic challenge via activating transforming growth factor-β (TGF-β)/Smad2 signaling pathway. Of note, lactate accelerated the lactylation of Snail1, a transcription factor of TGF-β, promoted its nuclear translocation to bind at the promoter of TGF-β, and upregulated TGF-β expression. Conclusion: In summary, we conclude that lactate acts as an important molecule that upregulates cardiac fibrosis after MI via induction of Snail1 lactylation and nuclear translocation to activate TGF-β/Smad2 pathway, resulting in EndMT.