Mechanosensitive PPAP2B Regulates Endothelial Responses to Atherorelevant Hemodynamic Forces

Abstract

Rationale PhosPhatidic-Acid-Phosphatase-type-2B (PPAP2B), an integral membrane protein that inactivates lysophosphatidic acid, was implicated in coronary artery disease (CAD) by genome-wide-association-studies (GWAS). However, it is unclear whether GWAS-identified CAD genes including PPAP2B participate in mechanotransduction mechanisms by which vascular endothelia respond to local athero-relevant hemodynamics that contribute to the regional nature of atherosclerosis. Objective To establish the critical role of PPAP2B in endothelial responses to hemodynamics. Methods and Results Reduced PPAP2B was detected in vivo in mouse and swine aortic arch endothelia exposed to chronic disturbed flow, and in mouse carotid artery endothelia subjected to surgically-induced acute disturbed flow. In humans, PPAP2B was reduced in the downstream part of carotid plaques where low shear stress prevails. In culture, reduced PPAP2B was measured in human aortic endothelial cells (HAEC) under athero-susceptible waveform mimicking flow in human carotid sinus. Flow-sensitive microRNA-92a and transcription factor KLF2 were identified as upstream inhibitor and activator of endothelial PPAP2B, respectively. PPAP2B suppression abrogated athero-protection of unidirectional flow; Inhibition of lysophosphatidic acid receptor 1 (LPAR1) restored the flow-dependent, anti-inflammatory phenotype in PPAP2B-deficient cells. PPAP2B inhibition resulted in myosin-light-chain phosphorylation and intercellular gaps, which were abolished by LPAR1/2 inhibition. Expression-quantitative-trait-locus-mapping demonstrated PPAP2B CAD risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in HAEC. Conclusions Athero-relevant flows dynamically modulate endothelial PPAP2B expression through miR-92a and KLF2. Mechano-sensitive PPAP2B plays a critical role in promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under athero-protective flow.

Integrated Bioinformatics Analysis Predicts the Key Genes Involved in Aortic Valve Calcification: From Hemodynamic Changes to Extracellular Remodeling

“…Furthermore, PLPP3 expression can be promoted by the flow-sensitive transcription factor KLF2 (Wu et al 2015), which, according to our study, was down-regulated in the in vitro experiments (fold change = 0.21). Normally, KLF2/PLPP3 maintains the formation of anti-flow endothelial cell alignment and contributes to the anti-inflammation/ adhesion phenotype of endothelial cells by inhibiting lysophosphatidic acid (LPA) and the downstream LPA receptor (LPAR) signaling pathway (Wu et al 2015). Interestingly, oxLDL-derived LPA was recently shown to promote the progression of AS through the LPAR1/NF-κB pathway (Nsaibia et al 2017).…”

“…In the present work, we predicted that PLPP3 might participate in the development of CAVD in a mechano-sensitive manner. Interestingly, Wu et al (2015) found that PLPP3 was a key gene in atherosclerosis due to its role in regulating endothelial responses to hemodynamic environments. Furthermore, PLPP3 expression can be promoted by the flow-sensitive transcription factor KLF2 (Wu et al 2015), which, according to our study, was down-regulated in the in vitro experiments (fold change = 0.21).…”

“…Interestingly, Wu et al (2015) found that PLPP3 was a key gene in atherosclerosis due to its role in regulating endothelial responses to hemodynamic environments. Furthermore, PLPP3 expression can be promoted by the flow-sensitive transcription factor KLF2 (Wu et al 2015), which, according to our study, was down-regulated in the in vitro experiments (fold change = 0.21). Normally, KLF2/PLPP3 maintains the formation of anti-flow endothelial cell alignment and contributes to the anti-inflammation/ adhesion phenotype of endothelial cells by inhibiting lysophosphatidic acid (LPA) and the downstream LPA receptor (LPAR) signaling pathway (Wu et al 2015).…”

Translating GWAS Into the Flow-Regulated Modulation of Lipid Mediator Signaling

“…In this issue of Circulation Research, Wu et al 2 report that an integral membrane protein previously described as a p120-catenin-associated integrin ligand localized to the adherens junction of endothelial cells 3 is implicated in endothelial cell responsiveness to flow. The protein in question is phosphatidic acid phosphatase type 2B (PPAP2B; also known as lipid phosphate phosphatase 3), and as the name suggests it is responsible for the dephosphorylation and inactivation of lipid substrates including lysophosphatidic acid (LPA), ceramide 1-phosphate, and sphingosine 1-phosphate.…”

“…Extracellular LPA can affect cellular responses via at least 6 G-protein coupled receptors (ie, LPA receptors 1-6) that are differentially expressed in various tissues. Wu et al 2 found that an antagonist of LPA receptor 1/3 restored the anti-inflammatory phenotype of PPAP2B-deficient endothelial cells exposed to atheroprotective flow in vitro. Also given that LPA receptor 3 was not detectable in the cells studied, it seems that the proatherogenic signals associated with LPA are initiated by the LPA receptor 1, a supposition confirmed by decreased expression of inflammatory molecules in cells treated with small interfering RNAs directed against LPA receptor 1.…”