Lysophosphatidylcholine induces apoptosis in human endothelial cells through a p38-mitogen-activated protein kinase-dependent mechanism

Takahashi, Masafumi; Okazaki, Hitoaki; Ogata, Yukiyo; Takeuchi, Koichi; Ikeda, Uichi; Shimada, Kazuyuki

doi:10.1016/s0021-9150(01)00674-8

Cited by 140 publications

(83 citation statements)

References 29 publications

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“…1). Downstream of DAG, we noticed that DAG could be converted to PC and then to LPC, another PKC activator, by PLA 2 (44). Because PLA 2 participates in several cell death models (12, 13), we investigated whether PLA 2 is involved in the lipoapoptosis of hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes

Han

Park

Shinzawa

et al. 2008

Journal of Lipid Research

215

192

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The pathogenesis of nonalcoholic steatohepatitis (NASH) is unclear, despite epidemiological data implicating FFAs. We studied the pathogenesis of NASH using lipoapoptosis models. Palmitic acid (PA) induced classical apoptosis of hepatocytes. PA-induced lipoapoptosis was inhibited by acyl-CoA synthetase inhibitor but not by ceramide synthesis inhibitors, suggesting that conversion products other than ceramide are involved. Phospholipase A 2 (PLA 2 ) inhibitors blocked PA-induced hepatocyte death, suggesting an important role for PLA 2 and its product lysophosphatidylcholine (LPC). Small interfering RNA for Ca 21 -independent phospholipase A 2 (iPLA 2 ) inhibited the lipoapoptosis of hepatocytes. PA increased LPC content, which was reversed by iPLA 2 inhibitors. Pertussis toxin or dominant-negative Ga i mutant inhibited hepatocyte death by PA or LPC acting through G-protein-coupled receptor (GPCR)/Ga i . PA decreased cardiolipin content and induced mitochondrial potential loss and cytochrome c translocation. Oleic acid inhibited PA-induced hepatocyte death by diverting PA to triglyceride and decreasing LPC content, suggesting that FFAs lead to steatosis or lipoapoptosis according to the abundance of saturated/unsaturated FFAs. LPC administration induced hepatitis in vivo. LPC content was increased in the liver specimens from NASH patients. These results demonstrate that LPC is a death effector in the lipoapoptosis of hepatocytes and suggest potential therapeutic values of PLA 2 inhibitors or GPCR/ Ga i inhibitors in

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes

Han

Park

Shinzawa

et al. 2008

Journal of Lipid Research

215

192

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“…Floating and/or adherent cells were collected, and DNA fragments were extracted, fractionated by 1.8% agarose gel electrophoresis, and stained with ethidium bromide. 30 …”

Section: Dna Ladderingmentioning

confidence: 99%

Antiapoptotic Effect of Endothelin-1 in Rat Cardiomyocytes In Vitro

Ogata¹,

Takahashi²,

Ueno³

et al. 2003

Hypertension

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Abstract-Apoptosis of cardiac myocytes is thought to be a feature of many pathological disorders, including congestive heart failure (CHF) and ischemic heart disease (IHD). Because recent investigations indicate that endothelin-1 (ET-1) plays an important role in CHF and IHD, we investigated the effect of ET-1 on cardiomyocyte apoptosis. The presence of apoptosis in rat cardiomyocytes (H9c2 and neonatal) was evaluated by morphological criteria, electrophoresis of DNA fragments, 4Ј,6Ј-diamidine-2Ј-phenylindole staining, and TUNEL analysis. ET-1, but not angiotensin II, prevented apoptosis induced by serum deprivation via ET A receptors in a dose-dependent manner (1 to 100 nmol/L). ET-1 also prevented cytochrome c release from mitochondria to the cytosol. The use of specific pharmacological inhibitors demonstrated that the antiapoptotic effect of ET-1 was mediated through a tyrosine kinase pathway (genistein and AG490) but not through protein kinase C (PKC; calphostin C), mitogen-activated protein kinases (PD98059 and SB203580), or PKA (KT5270) pathways. Adenovirus-mediated gene transfer of kinase-inactive (KI) c-Src reversed the antiapoptotic effect of ET-1. We further investigated whether Bcl-x L , an antiapoptotic molecule, would be upregulated by using a luciferase-based reporter system. ET-1 upregulated Bcl-x L , and this upregulation was inhibited by genistein or AG490 but not by calphostin C. The experiments with KI mutants for various tyrosine kinases revealed that c-Src and Pyk2 (but not JAK1, Jak2, Syk, and Tec) are involved in ET-1-induced upregulation of Bcl-x L expression. These findings suggest that ET-1 prevents apoptosis in cardiac myocytes through the ET A receptor and the subsequent c-Src/Bcl-x L -dependent pathway.

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“…For example, LPC increases the cytoplasmic free Ca ] i ) in endothelial cells, leukocytes, and macrophages (2,3). Recently, research has unveiled some roles of LPC in endothelial cells and smooth muscle cells (2,4,5). However, the action of LPC in monocytes has been poorly studied.…”

Section: Introductionmentioning

confidence: 99%

The Action Mode of Lysophosphatidylcholine in Human Monocytes

Yun

Okajima

2004

J Pharmacol Sci

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Abstract. To elucidate the action and signal transduction of lysophosphatidylcholine (LPC), we challenged a set of LPC on U937 human monocytes and found that LPC mobilized Ca 2+. The Ca2+ response was not blocked by pertussis toxin, an inhibitor of G i / o proteins, or by U73122, a phospholipase C inhibitor. Furthermore, the response was totally blocked by addition of EGTA to the extracellular media, suggesting that Ca 2+ influx across the plasma membrane was the only source of LPC-induced Ca 2+ response in the U937 cells. 16:0 and 18:0 LPC induced similar responses. Recently it has been suggested that two G protein-coupled receptors function as LPC receptors in the plasma membrane. RT-PCR analysis indicated that neither the G2A receptor nor the GPR4 receptor is expressed in the U937 monocytes. Our data suggests that another action mechanism of LPC may be involved in the LPC response in the U937 cells.

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Lysophosphatidylcholine induces apoptosis in human endothelial cells through a p38-mitogen-activated protein kinase-dependent mechanism

Cited by 140 publications

References 29 publications

Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes

Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes

Antiapoptotic Effect of Endothelin-1 in Rat Cardiomyocytes In Vitro

The Action Mode of Lysophosphatidylcholine in Human Monocytes

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