Abstract 14150: Glycolysis and Cardial Fibrosis

Introduction: Cardiac fibrosis is a significant global issue, which however has limited therapeutic options. 6 - phosphofructo - 2 - kinase/fructose - 2,6 - biphosphatase 3 (PFKFB3) is established to play a critical role in the process of glycolysis. However, its specific role in the pathogenesis of cardiac fibrosis is still not well understood. Hypothesis: PFKFB3 plays a critical role in cardial fibrosis. Methods: To determine the role of PFKFB3 in cardiac fibroblast (CF) activation and fibrosis, single - cell RNA sequencing analysis was applied to identify the metabolic changes of fibroblast subclusters in cardiomyopathy. PFKFB3 inhibition with genetic ( Pfkfb3 +/- ) mice or pharmacological (3PO) approach was used to demonstrate the role of PFKFB3 in cardiac fibrosis with animal models, induced by isoproterenol (ISO) or left coronary ligation. The role of PFKFB3 in primary CFs activation was confirmed by gene inhibition or overexpression. Recombinant PFKFB3 was used to test its extracellular role in CFs activation and inflammation. Serum PFKFB3 level was also tested from patients with cardiomyopathy. Results: We found that glycolysis changes most in cardiac myofibroblasts (myoCFs) in cardiomyopathy. PFKFB3 increased significantly in both cardiac fibrotic regions and myoCFs induced by TGF-β1. Inhibition of glycolysis, via several approaches, blunted TGF-β1-induced activation, proliferation and migration ability of myofibroblasts and demonstrated therapeutic benefit in cardiac fibrosis in mice. PFKFB3 released from myoCFs facilitated the activation of CFs and promoted the inflammatory response. Mechanistically, HIF-1α is required in TGF-β1 induced glycolysis. Plasm PFKFB3 was also found to be a biomarker for cardiac fibrosis in patients with cardiomyopathy. Conclusions: PFKFB3 is a candidate target for cardiac fibrosis.