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

Cell Calcium. 2023 Jun:112:102734. doi: 10.1016/j.ceca.2023.102734. Epub 2023 Apr 5.

Abstract

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.

Keywords: Calcium; Canonical transient receptor potential 6 channel; Endothelial migration; Hypercholesterolemia; Lysophosphatidylcholine; Phospholipase A2; iPLA2 inhibitor FKGK11.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcium* / metabolism
  • Female
  • Lysophosphatidylcholines / pharmacology
  • Male
  • Mice
  • Phospholipases A2
  • TRPC Cation Channels
  • TRPC6 Cation Channel
  • Transient Receptor Potential Channels*

Substances

  • TRPC6 Cation Channel
  • 1,1,1,2,2-pentafluoro-7-phenylheptan-3-one
  • Calcium
  • Lysophosphatidylcholines
  • Transient Receptor Potential Channels
  • Phospholipases A2
  • TRPC Cation Channels
  • Trpc6 protein, mouse