Lysophosphatidic acid receptor LPA₃ prevents oxidative stress and cellular senescence in Hutchinson–Gilford progeria syndrome

Abstract

Hutchinson–Gilford progeria syndrome (HGPS) is a rare laminopathy that produces a mutant form of prelamin A, known as Progerin, resulting in premature aging. HGPS cells show morphological abnormalities of the nuclear membrane, reduced cell proliferation rates, accumulation of reactive oxygen species (ROS), and expression of senescence markers. Lysophosphatidic acid (LPA) is a growth factor‐like lipid mediator that regulates various physiological functions via activating multiple LPA G protein‐coupled receptors. Here, we study the roles of LPA and LPA receptors in premature aging. We report that the protein level of LPA3 was highly downregulated through internalization and the lysosomal degradation pathway in Progerin‐transfected HEK293 cells. By treating Progerin HEK293 cells with an LPA3 agonist (OMPT, 1‐Oleoyl‐2‐O‐methyl‐rac‐glycerophosphothionate) and performing shRNA knockdown of the Lpa3r transcript in these cells, we showed that LPA3 activation increased expression levels of antioxidant enzymes, consequently inhibiting ROS accumulation and ameliorating cell senescence. LPA3 was shown to be downregulated in HGPS patient fibroblasts through the lysosomal pathway, and it was shown to be crucial for ameliorating ROS accumulation and cell senescence in fibroblasts. Moreover, in a zebrafish model, LPA3 deficiency was sufficient to cause premature aging phenotypes in multiple organs, as well as a shorter lifespan. Taken together, these findings identify the decline of LPA3 as a key contributor to the premature aging phenotypes of HGPS cells and zebrafish.

Inhibition of lysophosphatidic acid receptor 1-3 deteriorates experimental autoimmune encephalomyelitis by inducing oxidative stress

“…LPA signaling through LPAR3 increased expression levels of antioxidant enzymes, consequently inhibiting ROS accumulation and ameliorating cell senescence. Moreover, in a zebra sh model, LPA3 de ciency was su cient to cause premature aging phenotypes in multiple organs as well as a shorter lifespan (58). These results suggest that LPA or LPAR subtypes might exert signi cant positive or detrimental effects on neurodegeneration.…”

A Novel Function of the Lysophosphatidic Acid Receptor 3 (LPAR3) Gene in Zebrafish on Modulating Anxiety, Circadian Rhythm Locomotor Activity, and Short-Term Memory

“…This mutant line carries a 2 bp deletion (∆CA) and its corresponding protein was truncated and reduced from 353 to 135 amino acid residues ( Figure A1). This lpar3 KO fish displays an aging phenotype and was reported in our previous publication [37]. In this study, we aimed to explore the potential new function of the lpar3 gene on behaviors.…”

“…Therefore, LPAR3 may participate in the process to provide a novel treatment for promoting erythropoiesis [55]. In addition, LPAR3 has also been reported to play a role in embryo implantation and spacing in mice [56], mediate chemotaxis of immature murine dendritic cells to unsaturated LPA [57], regulate cellular functions during tumor progression in pancreatic cancer cells [58], and modulate the aging process [37].…”

Protective Effect of Shenqi Maixintong Capsule against ox‐LDL‐Induced Injury in RAW264.7 Macrophages

“…Our test results of SOD and MDA found that SMCs in different dose groups can increase the SOD value of cells treated with ox-LDL and decrease the MDA value. SOD and MDA are classic indicators of oxidative stress evaluation, and there are currently reports in the literature that oxidative stress can promote cellular senescence [42][43][44]. Studies show that oxidative stress accelerate telomere shortening or dysfunction and telomere shortening suppresses cancer by triggering senescence in normal cells [45][46][47].…”