Integrated Human Evaluation of the Lysophosphatidic Acid Pathway as a Novel Therapeutic Target in Atherosclerosis

Abstract

Variants in thePLPP3gene encoding for lipid phosphatephosphohydrolase 3 have been associated with susceptibilityto atherosclerosis independently of classical risk factors.PLPP3 inactivates lysophosphatidic acid (LPA), a pro-inflam-matory, pro-thrombotic product of phospholipase activity.Here we performed thefirst exploratory analysis of PLPP3,LPA, and LPA receptors (LPARs 1–6) in human atheroscle-rosis. PLPP3 transcript and protein were repressed whencomparing plaques versus normal arteries and plaques fromsymptomatic versus asymptomatic patients, and they werenegatively associated with risk of adverse cardiovascularevents. PLPP3 localized to macrophages, smooth muscle,and endothelial cells (ECs) in plaques. LPAR 2, 5, and espe-cially 6 showed increased expression in plaques, with LPAR6localized in ECs and positively correlated to PLPP3. Utilizingin situmass spectrometry imaging, LPA and its precursorswere found in the plaquefibrous cap, co-localizing withPLPP3 and LPAR6.In vitro, PLPP3 silencing in ECs underLPA stimulation resulted in increased expression of adhesionmolecules and cytokines. LPAR6 silencing inhibited LPA-induced cell activation, but not when PLPP3 was silencedsimultaneously. Our results show that repression of PLPP3plays a key role in atherosclerosis by promoting EC activation.Altogether, the PLPP3 pathway represents a suitable target forinvestigations into novel therapeutic approaches to ameliorateatherosclerosis.