Canagliflozin inhibits inflammasome activation in diabetic endothelial cells – Revealing a novel calcium-dependent anti-inflammatory effect of canagliflozin on human diabetic endothelial cells
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 c...
Saved in:
Published in | Biomedicine & pharmacotherapy Vol. 159; p. 114228 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
France
Elsevier Masson SAS
01.03.2023
Elsevier |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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.
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.
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).
CANA suppresses inflammasome activation by inhibition of (1) intracellular Ca2+ and (2) ERK1/2 phosphorylation, but not by ROS reduction.
[Display omitted]
•Canagliflozin inhibits TNF-α-induced inflammasome activation in diabetic endothelial cells.•The anti-inflammatory effect of canagliflozin is mediated via a novel Ca2+ inhibitory capacity.•Canagliflozin suppresses inflammasome activation independently of its ROS reducing effect.•Inhibition on ERK activation contributes to the anti-inflammatory effect of canagliflozin. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0753-3322 1950-6007 |
DOI: | 10.1016/j.biopha.2023.114228 |