iPLA2 inhibition blocks LysoPC-induced TRPC6 externalization and promotes Re-endothelialization of carotid injuries in hypercholesterolemic mice

• Published in: Cell calcium (Edinburgh) 2023-06, Vol.112, p.102734-102734, Article 102734
• Main Authors: Putta, Priya, Chaudhuri, Pinaki, Guardia-Wolff, Rocio, Rosenbaum, Michael A., Graham, Linda M.
• Format: Article
• Language: English
• Subjects: Animals; Calcium; Calcium - metabolism; Canonical transient receptor potential 6 channel; Endothelial migration; Female; Hypercholesterolemia; iPLA2 inhibitor FKGK11; Lysophosphatidylcholine; Lysophosphatidylcholines - pharmacology; Male; Mice; Phospholipase A2; Phospholipases A2; Transient Receptor Potential Channels; TRPC Cation Channels; TRPC6 Cation Channel
• ISSN: 0143-4160; 1532-1991
• DOI: 10.1016/j.ceca.2023.102734

•Calcium-independent phospholipase A2 (iPLA2) is selectively inhibited by FKGK11.•Calcium influx induced by lysophosphatidylcholine (lysoPC) is blocked by FKGK11.•FKGK11 blocks canonical transient receptor potential 6 channel externalization.•Reendothelialization of arterial injury in high fat-fed mice is promoted by FKGK11.•Endothelial healing after angioplasty in patients could be promoted by FKGK11. Lipid oxidation products, including lysophosphatidylcholine (lysoPC), accumulate at the site of arterial injury after vascular interventions and hinder re-endothelization. LysoPC activates calcium-permeable channels, specifically canonical transient receptor potential 6 (TRPC6) channels that induce a sustained increase in intracellular calcium ion concentration [Ca2+]i and contribute to dysregulation of the endothelial cell (EC) cytoskeleton. Activation of TRPC6 leads to inhibition of EC migration in vitro and delayed re-endothelization of arterial injuries in vivo. Previously, we demonstrated the role of phospholipase A2 (PLA2), specifically calcium-independent PLA2 (iPLA2), in lysoPC-induced TRPC6 externalization and inhibition of EC migration in vitro. The ability of FKGK11, an iPLA2-specific pharmacological inhibitor, to block TRPC6 externalization and preserve EC migration was assessed in vitro and in a mouse model of carotid injury. Our data suggest that FKGK11 prevents lysoPC-induced PLA2 activity, blocks TRPC6 externalization, attenuates calcium influx, and partially preserves EC migration in vitro. Furthermore, FKGK11 promotes re-endothelization of an electrocautery carotid injury in hypercholesterolemic mice. FKGK11 has similar arterial healing effects in male and female mice on a high-fat diet. This study suggests that iPLA2 is a potential therapeutic target to attenuate calcium influx through TRPC6 channels and promote EC healing in cardiovascular patients undergoing angioplasty. [Display omitted]