LPA rescues ER stress‐associated apoptosis in hypoxia and serum deprivation‐stimulated mesenchymal stem cells

Abstract

Poor viability of transplanted mesenchymal stem cells (MSCs) in the infracted heart has limited their therapeutic efficacy in cardiac repair after myocardial infarction. We previously demonstrated that hypoxia and serum deprivation (hypoxia/SD) induced mitochondria-dependent apoptosis in MSCs, while lysophosphatidic acid (LPA) could almost completely block this apoptotic process. However, the role of endoplasmic reticulum (ER) stress and its upstream signaling events in hypoxia/SD-induced MSC apoptosis remain largely unknown. Here we found that hypoxia/SD-induced MSC apoptosis was associated with ER stress, as shown by the induction of CHOP expression and procaspase-12 cleavage, while the effects were abrogated by LPA treatment, suggesting ER stress is also a target of LPA. Furthermore, hypoxia/SD induced p38 activation, inhibition of which resulted in decreases of apoptotic cells, procaspase-12 cleavage and mitochondrial cytochrome c release that function in parallel in MSC apoptosis. Unexpectedly, p38 inhibition enhanced hypoxia/SD-induced CHOP expression. Interestingly, p38 activation, a common process mediating various biological effects of LPA, was inhibited by LPA in this study, and the regulation of p38 pathway by LPA was dependent on LPA(1/3)/Gi/ERK1/2 pathway-mediated MKP-1 induction but independent of PI3K/Akt pathway. Collectively, our findings indicate that ER stress is a target of LPA to antagonize hypoxia/SD-induced MSC apoptosis, and the modulation of mitochondrial and ER stress-associated apoptotic pathways by LPA is at least partly dependent on LPA(1/3)/Gi/ERK/MKP-1 pathway-mediated p38 inhibition. This study may provide new anti-apoptotic targets for elevating the viability of MSCs for therapeutic potential of cardiac repair.

Activation of the δ-opioid receptor inhibits serum deprivation-induced apoptosis of human liver cells via the activation of PKC and the mitochondrial pathway

“…These findings are similar to the research conducted by Li et al (42). It has been demonstrated that the δ-opioid receptor agonist DADLE protects nerve cells against apoptosis through the mitochondrial pathway (43), but it remains to be determined whether this anti-apoptotic mechanism is involved in our system.…”

Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering

“…Micromolar concentrations of LPA protect neuronal precursors, 105 osteoblasts, osteoclasts, 88 rat and human MSCs, 4,5 and other cell types against SD/ H-and endoplasmic reticulum-stress induced apoptosis in vitro in a pertussis toxin-and PI3K-dependent manner. 82 Furthermore, these protective effects extend to MSCs injected in vivo 83 after preconditioning in medium containing LPA. Similarly, the development of nonlipid agonists of LPA 2 is underway for protecting ; LC-MS/MS 133 ; Radiolabeling 16 ; HPLC 130,134 LPA, lysophospholipid; ELISA, enzyme-linked immunosorbent assay; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography-mass spectrometry; MALDI-TOF, matrix-assisted laser desorption/ionization-time of flight.…”

“…81 Furthermore, LPA protects MSCs against apoptosis induced by ischemic conditions, likely through a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Aktmediated pathway. 4,5,82,83 In mature bone, LPA modulates cytoskeletal organization in osteoblasts and may stimulate extracellular matrix production and organization. 84 Osteoblasts increase ALP production in response to LPA, especially when concomitantly exposed to calcitriol, 7,76 indicating a role in osteoblast maturation.…”

Lysophosphatidylserine has Bilateral Effects on Macrophages in the Pathogenesis of Atherosclerosis

“…In particular, LysoPA promotes the release of the chemokine CXCL1 and the accumulation of macrophages in the endothelium of atherosclerotic lesions 3,24) , while LysoPC promotes the expression of IL-8, a proinflammatory and proadhesive chemokine 25) . Regarding ER stress, LysoPA reportedly attenuates ER stress and ER stress-associated apoptosis in murine mesenchymal stem cells 26) . Another interesting finding is that the effects of LysoPS on inflammatory mediators and ER stress were somehow dependent on the cell status.…”