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Zhai, Yajie

University of British Columbia

Every day, our heart pumps over 100,000 times delivering the oxygen and nutrients the body requires. In turn, constant and consistent ATP generation is essential. The heart normally utilizes ~30% glucose and ~70% fatty acids (FA) for ATP generation for the energy-demanding heart. One major FA source is from lipoprotein lipase (LPL)-derived FA. Circulating triglycerides (TG) in the blood stream are hydrolyzed by LPL on the vascular lumen of endothelial cells (EC) allowing for FA to be translocated to the cardiomyocyte (CMO). Notably LPL is synthesized in the CMO and transported to the vascular lumen of EC through unclear means. However, LPL movement from the CMO to the EC is dependent on the enzyme, heparanase (Hpa). Hpa, synthesized in the EC, is released and cleaves LPL bound to cell surface heparan sulfate proteoglycans (HSPG) on CMO. In this thesis, it is shown that 1) laminar flow (LF) instigates both latent (L-hpa) and active (A-hpa) heparanase release through an ATP- and purinergic (P2Y) receptor-dependent mechanism. 2) This LF-induced Hpa secretion mechanism is shared by the high glucose (HG)-induced Hpa secretion shown previously by our lab. 3) Non-canonical means of Hpa regulation is evident by decreases in cathepsin L (Cat L) activity following LF or HG. This enzyme is responsible for L-hpa to A-hpa conversion in the EC lysosomes and its downregulation would allow for increased L-hpa availability. 4) The downstream effects of increased L-hpa availability are made evident in a cardiac-specific VEGFB transgenic model. L-hpa is able to – increase VEGFA release and therefore increase angiogenesis, upregulate anti-apoptotic genes for cell survival, and play a role in cardiac hypertrophy. My thesis project spearheads the connection between laminar flow and cardiac metabolism and supports previously unappreciated roles of L-hpa.

Text

2023-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/81327

Pharmaceutical Sciences

University of British Columbia

UBCV

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