title: Effect of empagliflozin on cardiac biomarkers in a zebrafish model of heart failure: clues to the EMPA-REG OUTCOME trial?
abstract: The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin was recently reported to reduce heart failure-associated hospitalizations and cardiovascular mortality amongst individuals with type 2 diabetes at high cardiovascular risk. We sought to elucidate the underlying mechanism(s) for these protective effects using a validated zebrafish heart failure model to evaluate the impact of empagliflozin on the expression of biomarkers of heart failure and mortality. We used aristolochic acid (AA) to induce heart failure in developing cmlc2::GFP transgenic zebrafish embryos and monitored BNP signaling in nppb::Luc transgenic zebrafish with a luciferase reporter assay. Empagliflozin markedly reduced the morphological and functional cardiac changes induced by AA; dampened AA-enhanced expression of brain natriuretic peptide and atrial natriuretic peptide; and reduced embryonic mortality. Furthermore, morpholino-mediated knockdown of the slc5A2 gene mimicked the changes evoked by empagliflozin in developing zebrafish embryos previously exposed to AA. We report herein the first mechanistic data demonstrating a salutary benefit of SGLT2 inhibition on critical pathways of heart failure signaling. These findings provide important translational clues to the cardiovascular benefits documented in the EMPA-REG OUTCOME study.
authors.affiliation: Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Department of Medicine and Physiology, University of Toronto, 209 Victoria Street, LKSKI Rm 519, Toronto, ON, M5B 1T8, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.|Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, China.
authors.forename: Xingjuan
authors.initials: X
authors.lastname: Shi
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada. vermasu@smh.ca.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada. vermasu@smh.ca.|Department of Surgery, University of Toronto, Toronto, ON, Canada. vermasu@smh.ca.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. vermasu@smh.ca.
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
authors.affiliation: Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Department of Medicine and Physiology, University of Toronto, 209 Victoria Street, LKSKI Rm 519, Toronto, ON, M5B 1T8, Canada.
authors.forename: Junghwa
authors.initials: J
authors.lastname: Yun
authors.affiliation: Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Department of Medicine and Physiology, University of Toronto, 209 Victoria Street, LKSKI Rm 519, Toronto, ON, M5B 1T8, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Koroboshka
authors.initials: K
authors.lastname: Brand-Arzamendi
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada.|Division of Vascular Surgery, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, ON, Canada.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada.|Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Singh
authors.affiliation: Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, China.
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada.
authors.forename: Ankit
authors.initials: A
authors.lastname: Garg
authors.affiliation: Division of Cardiac Surgery, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, 30 Bond Street, Toronto, ON, M5B 1W8, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.affiliation: Zebrafish Centre for Advanced Drug Discovery, Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Department of Medicine and Physiology, University of Toronto, 209 Victoria Street, LKSKI Rm 519, Toronto, ON, M5B 1T8, Canada. wenx@smh.ca.|Institute of Medical Science, University of Toronto, Toronto, ON, Canada. wenx@smh.ca.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D034341:Aristolochic Acids / Q000494:pharmacology / Q000633:toxicity; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005260:Female; D005960:Glucosides / Q000494:pharmacology*; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*
chemical_list: D034341:Aristolochic Acids; D001559:Benzhydryl Compounds; D015415:Biomarkers; D005960:Glucosides; C092652:aristolochic acid C; C570240:empagliflozin
keywords: Biomarkers; Empagliflozin; Heart failure; Zebrafish