American Diabetes Association
Supplementary_Figure_v.2.pdf (272.83 MB)

Heparanase Stimulation of Physiological Cardiac Hypertrophy is Suppressed Following Chronic Diabetes Resulting in Cardiac Remodeling and Dysfunction

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posted on 2024-05-21, 18:27 authored by Chae Syng Lee, Rui Shang, Fulong Wang, Parisa Khayambashi, Hualin Wang, Gala Araujo, Karanjit Puri, Israel Vlodavsky, Bahira Hussein, Brian Rodrigues

Although endothelial cells control smooth muscle tone in coronary vessels, these cells also influence subjacent cardiomyocyte growth. As heparanase, with exclusive expression in endothelial cells, enables extracellular matrix remodeling, angiogenesis, metabolic reprogramming, and cell survival, it is conceivable that it could also encourage development of cardiac hypertrophy. Global heparanase overexpression resulted in physiological cardiac hypertrophy, likely an outcome of HSPG clustering and activation of hypertrophic signaling. The autocrine effect of heparanase to release neuregulin-1 may have also contributed to this effect. Hyperglycemia induced by streptozotocin-diabetes sensitized the heart to flow-induced release of heparanase and neuregulin-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 hypertrophy and heart dysfunction. Physiological cardiac hypertrophy was also observed in rats with cardiomyocyte-specific VEGFB overexpression. When perfused, hearts from these animals released significantly higher amounts of both heparanase and neuregulin-1. However, subjecting these animals to diabetes triggered robust transcriptome changes related to metabolism, and a transition to pathological hypertrophy. Our data suggest that 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 and a decline in cardiac function.


This work was supported by operating grants from the Canadian Institutes of Health Research [CIHR PJT-178134] and Diabetes Canada [OG-3-21-5585-BR].


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