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Wang, Hualin

University of British Columbia

Diabetes affects over half a billion people worldwide, with cardiovascular disease (CVD) as the leading cause of death among diabetes patients. Heart failure can result from diabetic cardiomyopathy (DCM). Altered cardiac metabolism contributes significantly to the development of DCM via augmenting fatty acid (FA) delivery and metabolism in the heart, resulting in oxidative stress and lipid accumulation in the heart. Inhibition of vascular endothelial growth factor B (VEGFB) has been reported to counter these factors associated with abnormal cardiac metabolism by inducing metabolic flexibility and preventing FA flux to the heart. In this study, the role of VEGFB in diabetes has been investigated as a potential therapy for DCM. Knockout (KO) of VEGFB globally in rats had subtle phenotype and transcriptome changes under normal conditions including decreased white adipose tissue (WAT) lipolysis, and decreased cardiac lipoprotein lipase (LPL) activity probably by hindering LPL translocation from cardiomyocyte (CMO) to coronary vasculature. With the induction of diabetes with streptozotocin (STZ), VEGFB KO rats displayed increased cardiac LPL activity compared to wildtype (WT) rats. This increase in LPL activity prevented animals from dyslipidemia and provided more LPL-derived FA, which inhibited excess FA oxidation, sustained angiogenesis and alleviated cell death in the heart. Inhibiting VEGFB could be a promising therapeutic strategy to address the current lack of mechanism-based treatments for DCM. Future studies on cardiomyocytes are anticipated to further explore the signaling pathways involved in VEGFB's regulation of LPL translocation, which will be crucial for advancing drug development.

Text

2024-10-09

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/89357

Pharmaceutical Sciences

University of British Columbia

UBCV

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