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Lee, Chae Syng

University of British Columbia

Endothelial cells (EC) influence subjacent cardiomyocyte metabolism and growth. Heparanase (Hpa), with exclusive expression in ECs, enables translocation of lipoprotein lipase (LPL) to the vascular lumen for hydrolysis of lipoprotein triglyceride, generating energy for cardiac contraction. We determined whether flow-mediated biophysical forces can cause EC to secrete Hpa. Despite the abundance of enzymatically active Hpa in the heart, it was the enzymatically inactive, latent Hpa that was exceptionally responsive to flow-induced release. EC exposed to orbital rotation exhibited a similar pattern of Hpa secretion, an effect that was reproduced by activation of the mechanosensor, Piezo1. The flow-mediated release of Hpa from EC required activation of both the purinergic receptor and protein kinase D. Hpa influenced cardiac metabolism by increasing cardiomyocyte LPL displacement along with subsequent replenishment. Flow-induced Hpa secretion was augmented following diabetes, and could explain the increased pool of LPL at the coronary lumen in these diabetic hearts. Hpa also facilitates angiogenesis, metabolic reprogramming, and cell survival, an environment favorable for cardiomyocyte growth. Hpa overexpression resulted in physiological cardiac hypertrophy, likely an outcome on HSPG clustering and activation of hypertrophic signaling. The autocrine effect of Hpa to release neuregulin-1 (NRG-1) may have also contributed to this effect. Hyperglycemia induced by streptozotocin-diabetes sensitized the heart to flow-induced release of Hpa and NRG-1. Despite this excess secretion, progression of diabetes caused significant gene expression changes related to mitochondrial metabolism and cell death that led to development of pathological cardiac hypertrophy. Physiological cardiac hypertrophy was also observed in rats with VEGFB overexpression. When perfused, hearts from these animals released significantly higher amounts of both Hpa and NRG-1. However, subjecting these animals to diabetes triggered robust genomic changes related to metabolism, and a transition to pathological hypertrophy. Overall, flow-induced mechanosensing and its dynamic control of cardiac metabolism to generate ATP is exquisitely adapted to respond to disease conditions, like diabetes. Additionally, we establish another novel function of Hpa to promote physiological cardiac hypertrophy. In the absence of mechanisms that support cardiac energy generation and prevention of cell death, as seen following diabetes, there is a transition from physiological to pathological cardiac hypertrophy.

Text

2024-08-21

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88980

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/