2. Academic Validation
  3. Canagliflozin inhibits inflammasome activation in diabetic endothelial cells - Revealing a novel calcium-dependent anti-inflammatory effect of canagliflozin on human diabetic endothelial cells

Canagliflozin inhibits inflammasome activation in diabetic endothelial cells - Revealing a novel calcium-dependent anti-inflammatory effect of canagliflozin on human diabetic endothelial cells

  • Biomed Pharmacother. 2023 Jan 7;159:114228. doi: 10.1016/j.biopha.2023.114228.
Xiaoling Li 1,  Raphaela P Kerindongo 2,  Benedikt Preckel 3,  Jan-Ole Kalina 4,  Markus W Hollmann 5,  Coert J Zuurbier 6,  Nina C Weber 7
Affiliations

Affiliations

  • 1 Amsterdam, University Medical Centers, location AMC, Department of Anesthesiology - L.E.I.C.A, Cardiovascular Science, Meibergdreef 11, 1105 AZ Amsterdam, the Netherlands. Electronic address: x.li1@amsterdamumc.nl.
  • 2 Amsterdam, University Medical Centers, location AMC, Department of Anesthesiology - L.E.I.C.A, Cardiovascular Science, Meibergdreef 11, 1105 AZ Amsterdam, the Netherlands. Electronic address: r.p.kerindongo@amsterdamumc.nl.
  • 3 Amsterdam, University Medical Centers, location AMC, Department of Anesthesiology - L.E.I.C.A, Cardiovascular Science, Meibergdreef 11, 1105 AZ Amsterdam, the Netherlands. Electronic address: b.preckel@amsterdamumc.nl.
  • 4 Amsterdam, University Medical Centers, location AMC, Department of Anesthesiology - L.E.I.C.A, Cardiovascular Science, Meibergdreef 11, 1105 AZ Amsterdam, the Netherlands. Electronic address: j.o.kalina@amsterdamumc.nl.
  • 5 Amsterdam, University Medical Centers, location AMC, Department of Anesthesiology - L.E.I.C.A, Cardiovascular Science, Meibergdreef 11, 1105 AZ Amsterdam, the Netherlands. Electronic address: m.w.hollmann@amsterdamumc.nl.
  • 6 Amsterdam, University Medical Centers, location AMC, Department of Anesthesiology - L.E.I.C.A, Cardiovascular Science, Meibergdreef 11, 1105 AZ Amsterdam, the Netherlands. Electronic address: c.j.zuurbier@amsterdamumc.nl.
  • 7 Amsterdam, University Medical Centers, location AMC, Department of Anesthesiology - L.E.I.C.A, Cardiovascular Science, Meibergdreef 11, 1105 AZ Amsterdam, the Netherlands. Electronic address: n.c.hauck@amsterdamumc.nl.
PMID: 36623448 DOI: 10.1016/j.biopha.2023.114228
Abstract

Background: Canagliflozin (CANA) shows anti-inflammatory and anti-oxidative effects on endothelial cells (ECs). In diabetes mellitus (DM), excessive Reactive Oxygen Species (ROS) generation, increased intracellular calcium (CA2+) and enhanced extracellular signal regulated kinase (ERK) 1/2 phosphorylation are crucial precursors for inflammasome activation. We hypothesized that: (1) CANA prevents the TNF-α triggered ROS generation in ECs from diabetic donors and in turn suppresses the inflammasome activation; and (2) the anti-inflammatory effect of CANA is mediated via intracellular CA2+ and ERK1/2.

Methods: Human coronary artery endothelial cells from donors with DM (D-HCAECs) were pre-incubated with either CANA or vehicle for 2 h before exposure to 50 ng/ml TNF-α for 2-48 h. NAC was applied to scavenge ROS, BAPTA-AM to chelate intracellular CA2+, and PD 98059 to inhibit the activation of ERK1/2. Live cell imaging was performed at 6 h to measure ROS and intracellular CA2+. At 48 h, ELISA and infra-red western blot were applied to detect IL-1β, NLRP3, pro-caspase-1 and ASC.

Results: 10 µM CANA significantly reduced TNF-α related ROS generation, IL-1β production and NLRP3 expression (P all <0.05), but NAC did not alter the inflammasome activation (P > 0.05). CANA and BAPTA both prevented intracellular CA2+ increase in cells exposed to TNF-α (P both <0.05). Moreover, BAPTA and PD 98059 significantly reduced the TNF-α triggered IL-1β production as well as NLRP3 and pro-caspase-1 expression (P all <0.05).

Conclusion: CANA suppresses inflammasome activation by inhibition of (1) intracellular CA2+ and (2) ERK1/2 phosphorylation, but not by ROS reduction.

Keywords

Canagliflozin (CANA); Extracellular signal regulated kinase (ERK) 1/2 phosphorylation; Interleukin (IL)− 1β; Intracellular calcium (Ca(2+)); Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome; Reactive oxygen species (ROS).

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