Restoration of endothelial glycocalyx is a promising therapeutic approach for heart failure

Background The endothelial glycocalyx (EGx) is a thin layer on endothelial cells that plays vital roles in water absorption, vessel lubrication, mechanotransduction, vascular permeability, and leukocyte adhesion. Heparanase (Hpa) is an enzyme that degrades EGx, and under conditions like ischemia, EGx degradation impairs vascular permeability and increases leukocyte adhesion, affecting cardiovascular disease treatments. Hypothesis: Acute myocardial ischemia (AMI) leads to significant degradation of the EGx layer, negatively impacting left ventricular ejection fraction (LVEF), potentially through the action of Hpa. Aims 1.To Investigate EGx alterations during acute myocardial infarction (AMI).2. To explore the role of Hpa in EGx degradation in AMI and in Human Umbilical Cord Endothelial Cells (HUVECs) overexpressing Hpa. 3. To develop strategies to protect or restore the EGx layer as a treatment for ischemic diseases. Methods AMI was induced in rats by ligating the LAD coronary artery. Human umbilical vein endothelial cells (HUVECs) overexpressing Hpa were used for in vitro experiments. EGx degradation was analyzed using transmission electron microscopy (TEM), immunofluorescence, ELISA for EGx shedding, qPCR, and Western blotting to assess the enzymes involved in EGx biosynthesis and degradation. Results Two weeks post-AMI, rats showed a significant reduction in LVEF and a 19-fold increase in serum levels of shed Syndecan1 (SDC1) (an EGx degradation marker). Transmission electron microscopy TEM images revealed thinning and disruption of the EGx layer in AMI hearts (40 nm vs. 110 nm in sham). Hpa activity and mRNA expression were significantly elevated. Inhibition of Hpa with the heparanase inhibitor, PG545 reduced enzyme activity but did not prevent SDC1 shedding. In ischemic HUVECs, Hpa mRNA increased six fold, and overexpression of Hpa caused complete EGx degradation. Hpa silencing restored the EGx layer and suppressed SDC1 shedding. Conclusion Hpa is crucial in EGx degradation during ischemic heart failure. Inhibiting Hpa may provide a promising therapeutic approach to prevent EGx degradation in ischemic diseases.