title: Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts.
abstract: During myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I-201 (a STAT3 inhibitor), or phlorizin + S3I-201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased levels of superoxide and nitrotyrosine, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Although phlorizin decreased myofibroblast infiltration, the effect of dapagliflozin on attenuated myofibroblast infiltration was significantly higher than phlorizin. The effects of SGLT2 inhibitors on cardiac fibrosis were nullified by adding S3I-201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL-10 levels can be reversed by 3-morpholinosydnonimine, a peroxynitrite generator. Taken together, these observations provide a novel mechanism of SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during postinfarction remodeling.
authors.affiliation: Department of Medicine, Cardiology Section, An Nan Hospital, China Medical University, Tainan, Taiwan; Department of Medicine, China Medical University, Taichung, Taiwan; Cardiovascular Research Laboratory, China Medical University Hospital, Taichung, Taiwan; Department of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: tsungm.lee@msa.hinet.net.
authors.forename: Tsung-Ming
authors.initials: TM
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, School of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taiwan.
authors.forename: Nen-Chung
authors.initials: NC
authors.lastname: Chang
authors.affiliation: Bioinnovation Center, Hualien, Taiwan; Tzu Chi foundation, Hualien, Taiwan; Department of Neurosurgery, Tzu Chi University Hospital, Hualien, Taiwan.
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage*; D005355:Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005960:Glucosides / Q000008:administration & dosage*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics*; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001559:Benzhydryl Compounds; D005960:Glucosides; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C494088:Stat3 protein, rat; D016753:Interleukin-10; C529054:dapagliflozin
keywords: Interleukin-10; M2 macrophage; Reactive oxygen and nitrogen species; Signal transducer and activator of transcription 3; Sodium-glucose cotransporter 2 inhibitor