P110α and P110δ catalytic subunits of PI3 kinase regulate lysophosphatidylcholine-induced TRPC6 externalization

Abstract

Lipid oxidation products, including lysophosphatidylcholine (lysoPC) inhibit endothelial cell (EC) migration in vitro and impair EC healing of arterial injuries in vivo, in part by activating phosphatidylinositol 3-kinase (PI3K), which increases the externalization of canonical transient receptor potential 6 (TRPC6) channels and the subsequent increase in intracellular calcium. Inhibition of PI3K is a potential method to decrease TRPC6 activation and restore migration, but PI3K is involved in multiple intracellular signaling pathways and has multiple downstream effectors. The goal of this study is to identify the specific p110 catalytic subunit isoforms responsible for lysoPC-induced TRPC6 externalization to identify a target for intervention while minimizing impact on alternative signaling pathways. Down-regulation of the p110α and p110δ isoforms, but not the p110β or p110γ isoforms, with small interfering RNA significantly decreased phosphatidylinositol (3,4,5)-trisphosphate production and TRPC6 externalization, and significantly improved EC migration in the presence of lysoPC. These results identify an additional role of p110α in EC and reveal for the first time a specific role of p110δ in EC, providing a foundation for subsequent in vivo studies to investigate the impact of p110 isoform inhibition on arterial healing after injury.

Enhanced Orai1-mediated store-operated Ca2+ channel/calpain signaling contributes to high glucose-induced podocyte injury

“…However, the Ca 2+ -dependent proteinase calpain seems to be a master effector serving multiple Ca 2+ signaling pathways. In addition to SOCE pathway reported by the present study, both TRPC5 and TRPC6 Ca 2+ signals also activate calpain pathway (36,37,52). Thus, Ca 2+ signals from different sources in podocytes may interact with each other at a site of a particular signaling pathway.…”

GDF11 alleviates neointimal hyperplasia in a rat model of artery injury by regulating endothelial NLRP3 inflammasome activation and rapid re-endothelialization

“…Lysophosphatidylcholine (lysoPC), a bioactive phospholipid generated by various biological processes, is abundant in plasma and accumulates in damaged blood vessels [ 18 , 19 ]. Previous studies have demonstrated that its inhibition of vascular endothelial cell function is unfavorable for the restoration of endothelial integrity after injury [ 20 , 21 ]. Moreover, studies have shown that lysoPC is associated with the activation of endothelial NLRP3 inflammasomes [ 22 , 23 ].…”

Lysophosphatidylcholine inhibits lung cancer cell proliferation by regulating fatty acid metabolism enzyme long‐chain acyl‐coenzyme A synthase 5

“…Biological functions of lysoPC vary among cell types, promoting atherosclerotic plaque formation and inflammatory reaction, enhancing anti‐infection response, regulating blood glucose and affecting tumour invasion and metastasis 55 . LysoPC inhibited endothelial cell migration and healing of arterial injuries partially through the activation of PI3K p110α and p110δ isoforms and promoted phagosome maturation and production of inflammatory mediators through PI3K and p38MAP 56,57 . LysoPC activated the ERK pathway to regulate the production of ROS and Ca ++ in mitochondria 58 .…”

“… 55 LysoPC inhibited endothelial cell migration and healing of arterial injuries partially through the activation of PI3K p110α and p110δ isoforms and promoted phagosome maturation and production of inflammatory mediators through PI3K and p38MAP. 56 , 57 LysoPC activated the ERK pathway to regulate the production of ROS and Ca ++ in mitochondria. 58 In lung cancer cells, lysoPC could elevate mRNA and protein expression of PI3K‐ and ERK‐signal pathways associated with 10 kinases in lysoPC‐treated cells, presenting multi‐kinase‐based molecular mechanisms (Figure S6I,J ).…”