PMID- 29588466
OWN - NLM
STAT- MEDLINE
DCOM- 20191007
LR  - 20231115
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 8
IP  - 1
DP  - 2018 Mar 27
TI  - Canagliflozin inhibits interleukin-1beta-stimulated cytokine and chemokine secretion 
      in vascular endothelial cells by AMP-activated protein kinase-dependent and 
      -independent mechanisms.
PG  - 5276
LID - 10.1038/s41598-018-23420-4 [doi]
LID - 5276
AB  - Recent clinical trials of the hypoglycaemic sodium-glucose co-transporter-2 
      (SGLT2) inhibitors, which inhibit renal glucose reabsorption, have reported 
      beneficial cardiovascular outcomes. Whether SGLT2 inhibitors directly affect 
      cardiovascular tissues, however, remains unclear. We have previously reported 
      that the SGLT2 inhibitor canagliflozin activates AMP-activated protein kinase 
      (AMPK) in immortalised cell lines and murine hepatocytes. As AMPK has 
      anti-inflammatory actions in vascular cells, we examined whether SGLT2 inhibitors 
      attenuated inflammatory signalling in cultured human endothelial cells. 
      Incubation with clinically-relevant concentrations of canagliflozin, but not 
      empagliflozin or dapagliflozin activated AMPK and inhibited IL-1beta-stimulated 
      adhesion of pro-monocytic U937 cells and secretion of IL-6 and monocyte 
      chemoattractant protein-1 (MCP-1). Inhibition of MCP-1 secretion was attenuated 
      by expression of dominant-negative AMPK and was mimicked by the direct AMPK 
      activator, A769662. Stimulation of cells with either canagliflozin or A769662 had 
      no effect on IL-1beta-stimulated cell surface levels of adhesion molecules or 
      nuclear factor-kappaB signalling. Despite these identical effects of canagliflozin 
      and A769662, IL-1beta-stimulated IL-6/MCP-1 mRNA was inhibited by canagliflozin, but 
      not A769662, whereas IL-1beta-stimulated c-jun N-terminal kinase phosphorylation was 
      inhibited by A769662, but not canagliflozin. These data indicate that 
      clinically-relevant canagliflozin concentrations directly inhibit endothelial 
      pro-inflammatory chemokine/cytokine secretion by AMPK-dependent and -independent 
      mechanisms without affecting early IL-1beta signalling.
FAU - Mancini, Sarah J
AU  - Mancini SJ
AD  - Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary 
      and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
FAU - Boyd, Daria
AU  - Boyd D
AD  - Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary 
      and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
FAU - Katwan, Omar J
AU  - Katwan OJ
AD  - Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary 
      and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
AD  - Department of Biochemistry, College of Medicine, University of Diyala, Baqubah, 
      Iraq.
FAU - Strembitska, Anastasiya
AU  - Strembitska A
AD  - Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary 
      and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
FAU - Almabrouk, Tarek A
AU  - Almabrouk TA
AD  - Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary 
      and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
AD  - Medical School, University of Zawia, Zawia, Libya.
FAU - Kennedy, Simon
AU  - Kennedy S
AUID- ORCID: 0000-0003-0887-5840
AD  - Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary 
      and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.
FAU - Palmer, Timothy M
AU  - Palmer TM
AD  - School of Pharmacy and Medical Sciences, University of Bradford, Bradford, West 
      Yorkshire, BD7 1DP, UK.
FAU - Salt, Ian P
AU  - Salt IP
AUID- ORCID: 0000-0003-0055-3724
AD  - Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary 
      and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK. 
      Ian.Salt@glasgow.ac.uk.
LA  - eng
GR  - PG/12/1/29276/BHF_/British Heart Foundation/United Kingdom
GR  - PG/13/82/30483/BHF_/British Heart Foundation/United Kingdom
GR  - FS/14/61/31284/BHF_/British Heart Foundation/United Kingdom
GR  - FS/16/55/32731/BHF_/British Heart Foundation/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180327
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Chemokines)
RN  - 0 (Cytokines)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Sodium-Glucose Transporter 2 Inhibitors)
RN  - 0SAC974Z85 (Canagliflozin)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*immunology
MH  - Animals
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Canagliflozin/*pharmacology
MH  - Cells, Cultured
MH  - Chemokines/immunology
MH  - Cytokines/*immunology
MH  - Endothelial Cells/*drug effects/immunology
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Interleukin-1beta/*antagonists & inhibitors/immunology
MH  - Mice
MH  - Sodium-Glucose Transporter 2 Inhibitors/*pharmacology
PMC - PMC5869674
COIS- The authors declare no competing interests.
EDAT- 2018/03/29 06:00
MHDA- 2019/10/08 06:00
PMCR- 2018/03/27
CRDT- 2018/03/29 06:00
PHST- 2017/10/09 00:00 [received]
PHST- 2018/03/12 00:00 [accepted]
PHST- 2018/03/29 06:00 [entrez]
PHST- 2018/03/29 06:00 [pubmed]
PHST- 2019/10/08 06:00 [medline]
PHST- 2018/03/27 00:00 [pmc-release]
AID - 10.1038/s41598-018-23420-4 [pii]
AID - 23420 [pii]
AID - 10.1038/s41598-018-23420-4 [doi]
PST - epublish
SO  - Sci Rep. 2018 Mar 27;8(1):5276. doi: 10.1038/s41598-018-23420-4.