Key result
Fluid shear-stress induced the secretion of latent heparanase from endothelial cells, regulating cardiac metabolism by increasing cardiomyocyte lipoprotein lipase displacement, which was augmented in diabetes.
Why the study?
It was unknown whether flow-mediated biophysical forces cause endothelial cells to secrete heparanase and thereby regulate cardiac metabolism.
Endothelial cells sense fluid shear stress and release heparanase to regulate cardiac metabolism via lipoprotein lipase, a mechanosensing pathway that is augmented in diabetes.
Flow may regulate cardiac energy supply via endothelial heparanase; leaves open in vivo or clinical relevance.
Background Lipoprotein lipase (LPL)-derived fatty acid is a major source of energy for cardiac contraction. Synthesized in cardiomyocytes, LPL requires translocation to the vascular lumen for hydrolysis of lipoprotein triglyceride, an action mediated by endothelial cell (EC) release of heparanase. We determined whether flow-mediated biophysical forces can cause ECs to secrete heparanase and thus regulate cardiac metabolism. Methods and Results Isolated hearts were retrogradely perfused. Confluent rat aortic ECs were exposed to laminar flow using an orbital shaker. Cathepsin L activity was determined using gelatin-zymography. Diabetes was induced in rats with streptozotocin. Despite the abundance of enzymatically active heparanase in the heart, it was the enzymatically inactive, latent heparanase that was exceptionally responsive to flow-induced release. EC exposed to orbital rotation exhibited a similar pattern of heparanase secretion, an effect that was reproduced by activation of the mechanosensor, Piezo1. The laminar flow-mediated release of heparanase from EC required activation of both the purinergic receptor and protein kinase D, a kinase that assists in vesicular transport of proteins. Heparanase influenced cardiac metabolism by increasing cardiomyocyte LPL displacement along with subsequent replenishment. The flow-induced heparanase secretion was augmented following diabetes and could explain the increased heparin-releasable pool of LPL at the coronary lumen in these diabetic hearts. Conclusions ECs sense fluid shear-stress and communicate this information to subjacent cardiomyocytes with the help of heparanase. This flow-induced mechanosensing and its dynamic control of cardiac metabolism to generate ATP, using LPL-derived fatty acid, is exquisitely adapted to respond to disease conditions, like diabetes.
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Lee et al. (2022) studied Diabetes. Laminar flow / fluid shear-stress was evaluated on Heparanase secretion and lipoprotein lipase displacement. Fluid shear-stress induced the secretion of latent heparanase from endothelial cells, regulating cardiac metabolism by increasing cardiomyocyte lipoprotein lipase displacement, which was augmented in diabetes.
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