PLD1 Promotes Reactive Oxygen Species Production in Vascular Smooth Muscle Cells and Injury-Induced Neointima Formation

Authors

Ming Cai
Ziqing Wang
Thi Thu Trang Luu
Dakai Zhang
Brian Finke
Jingquan He
Li Wei Rachel Tay
Gilbert Di Paolo
Guangwei Du

Publication Date

1-1-2022

Journal

Molecular and Cell Biology of Lipids

Abstract

Phospholipase D (PLD) generates the signaling lipid phosphatidic acid (PA) and has been known to mediate proliferation signal in vascular smooth muscle cells (VSMCs). However, it remains unclear how PLD contributes to vascular diseases. VSMC proliferation directly contributes to the development and progression of cardiovascular disease, such as atherosclerosis and restenosis after angioplasty. Using the mouse carotid artery ligation model, we find that deletion of Pld1 gene inhibits neointima formation of the injuried blood vessels. PLD1 deficiency reduces the proliferation of VSMCs in both injured artery and primary cultures through the inhibition of ERK1/2 and AKT signals. Immunohistochemical staining of injured artery and flow cytometry analysis of VSMCs shows a reduction of the levels of reactive oxygen species (ROS) in Pld1-/- VSMCs. An increase of intracellular ROS by hydrogen peroxide stimulation restored the reduced activities of ERK and AKT in Pld1-/- VSMCs, whereas a reduction of ROS by N-acetyl-l-cysteine (NAC) scavenger lowered their activity in wild-type VSMCs. These results indicate that PLD1 plays a critical role in neointima, and that PLD1 mediates VSMC proliferation signal through promoting the production of ROS. Therefore, inhibition of PLD1 may be used as a therapeutic approach to suppress neointimal formation in atherosclerosis and restenosis after angioplasty.

Keywords

Animals, Atherosclerosis, Carotid Arteries, Carotid Artery Injuries, Disease Models, Animal, Humans, Mice, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Neointima, Phospholipase D, Reactive Oxygen Species, PLD1, VSMC, proliferation, neointima

DOI

10.1016/j.bbalip.2021.159062

PMID

34610470

PMCID

PMC11960192

PubMedCentral® Posted Date

4-1-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes