Journal
BIOCHEMICAL PHARMACOLOGY
Volume 170, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2019.113677
Keywords
Empagliflozin; Metabolomics; Heart; Glycerophospholipids; Sphingolipids; Ceramides
Categories
Funding
- Boehringer Ingelheim Pharma GmbH Co
- FEDER Funds
- MSCA-RISE-H2020 Programme [734899]
- Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III, Madrid, Spain [PI15/00681, PI17/00409, PI18/00821]
- Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III, Madrid, Spain [RETICS Programme] [RD16/0012/0014]
- Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III, Madrid, Spain [CIBERCV]
- Xunta de Galicia, FPU Program of the Spanish Ministry of Science, Innovation and Universities (Spain)
- Spanish Society of Cardiology
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The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial made evident the potentiality of pharmacological sodium-glucose cotransporter 2 (SGLT2) inhibition for treating patients with diabetes and cardiovascular disease. Since the effect of empagliflozin or other SGLT2 inhibitors on the whole cardiac metabolic profile was never analysed before, and with the purpose to contribute to elucidate the benefits at cardiac level of the use of empagliflozin, we explored the effect of the treatment with empagliflozin for six weeks on the cardiac metabolomic profile of Zucker diabetic fatty rats, a model of early stage T2DM, using untargeted metabolomics approach. Empagliflozin reduced significantly the cardiac content of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (major bioactive contributing factors linking insulin resistance to cardiac damage) and decreased the cardiac content of the fatty acid transporter cluster of differentiation 36 (CD36); induced significant decreases of the cardiac levels of essential glycolysis intermediaries 2,3-bisphosphoglycerate and phosphoenolpyruvate, and regulated the abundance of several amino acids of relevance as tricarboxylic acid suppliers and/or in the metabolic control of the cardiac function as glutamic acid, gamma-aminobutyric acid and sarcosine. Empagliflozin treatment activated the cardioprotective master regulator of cellular energy homeostasis AMP-activated protein kinase (AMPK) and enhanced autophagy at cardiac level, while it decreased significantly the cardiac mRNA levels of the pro-inflammatory cytokines interleukin-6 (IL-6), chemerin, TNF-alpha and MCP-1, reinforcing the hypothesis of a direct role for empagliflozin in attenuating cardiac inflammation. Our results provide an advancement on the knowledge of the mechanisms linking the therapy with empagliflozin with protective effects on the development of cardiometabolic diseases whose course is associated with remarkable cardiac bioenergetics dysregulation and disarrangement in cardiac metabolome and lipidome.
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