Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart
| Autor: | Brian Rodrigues, Chae Syng Lee, Ibrahim Sultan, Oscar Seira, Rui Shang, Markus Räsänen, Yajie Zhai, Bahira Hussein, Robert Boushel, Kari Alitalo, Nathaniel Lal, Karanjit Puri |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Male
Vascular Endothelial Growth Factor B medicine.medical_specialty Physiology Endocrinology Diabetes and Metabolism medicine.medical_treatment Transgene 030204 cardiovascular system & hematology Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Physiology (medical) Internal medicine medicine Animals Insulin Cells Cultured 030304 developmental biology 0303 health sciences Lipoprotein lipase biology Myocardium Cardiac muscle Heart Rats Up-Regulation Enzyme Activation Vascular endothelial growth factor B Lipoprotein Lipase Insulin receptor medicine.anatomical_structure Endocrinology Lysophosphatidylcholine Lipotoxicity chemistry Organ Specificity biology.protein Female Insulin Resistance Rats Transgenic |
| Zdroj: | American Journal of Physiology-Endocrinology and Metabolism. 321:E753-E765 |
| ISSN: | 1522-1555 0193-1849 |
| DOI: | 10.1152/ajpendo.00219.2021 |
| Popis: | Cardiac muscle uses multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favors glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signaling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms, in the absence of any in vivo confounding regulators of cardiac metabolism, demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example, diabetes.NEW & NOTEWORTHY In hearts overexpressing vascular endothelial growth factor B (VEGFB), besides its known angiogenic response, multiple regulatory mechanisms lowered coronary LPL. This was accompanied by limited cardiac lipid metabolite accumulation with an augmentation of cardiac insulin action. Our data for the first time links VEGFB to coronary LPL in regulation of cardiac metabolism. VEGFB may be cardioprotective in metabolic disorders like diabetes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|