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Calcium-independent phospholipase A2-catalyzed plasmalogen hydrolysis in hypoxic human coronary artery endothelial cells.

Abstract
Thrombin stimulation of human coronary artery endothelial cells (HCAEC) results in activation of a membrane-associated, calcium-independent phospholipase A(2) (iPLA(2)) that selectively hydrolyzes membrane plasmalogen phospholipids. Rupture of an atherosclerotic plaque and occlusion of the coronary vasculature results in a coronary ischemic event in which HCAEC in the ischemic area would be exposed to dramatic decreases in oxygen tension in addition to thrombin exposure. We exposed HCAEC to hypoxia in the presence or absence of thrombin stimulation and measured iPLA(2) activation, membrane phospholipid hydrolysis, and the accumulation of biologically active phospholipid metabolites. HCAEC exposed to hypoxia, thrombin stimulation, or a combination of the two conditions demonstrated an increase in iPLA(2) activity and an increase in arachidonic acid release from plasmenylcholine. Thrombin stimulation of normoxic HCAEC did not result in an accumulation of choline lysophospholipids, but hypoxia alone and in combination with thrombin stimulation led to a significant accumulation of lysoplasmenylcholine (LPlsCho). We propose that the presence of hypoxia inhibits LPlsCho catabolism, at least in part, as a result of the accumulation of long-chain acylcarnitines. The combination of increased production and decreased catabolism of LPlsCho is necessary for its accumulation. Pretreatment with bromoenol lactone to inhibit iPLA(2) blocked membrane phospholipid hydrolysis and production of membrane phospholipid-derived metabolites. The increase in iPLA(2) activity and the subsequent accumulation of membrane phospholipid-derived metabolites in HCAEC exposed to hypoxia or thrombin stimulation alone, and particularly in combination, have important implications in inflammation and arrhythmogenesis in atherosclerosis/thrombosis and subsequent myocardial ischemia.
AuthorsMaureen C Meyer, Jane McHowat
JournalAmerican journal of physiology. Cell physiology (Am J Physiol Cell Physiol) Vol. 292 Issue 1 Pg. C251-8 (Jan 2007) ISSN: 0363-6143 [Print] United States
PMID16943248 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Lysophospholipids
  • Naphthalenes
  • Plasmalogens
  • Pyrones
  • choline plasmalogens
  • lysoplasmalogens
  • Arachidonic Acid
  • 6-(bromomethylene)tetrahydro-3-(1-naphthaleneyl)-2H-pyran-2-one
  • Phospholipases A
  • Group VI Phospholipases A2
  • PLA2G6 protein, human
  • Phospholipases A2
  • Thrombin
Topics
  • Arachidonic Acid (metabolism)
  • Catalysis
  • Cells, Cultured
  • Coronary Vessels (drug effects, metabolism)
  • Endothelial Cells (drug effects, metabolism)
  • Enzyme Activation
  • Group VI Phospholipases A2
  • Humans
  • Hydrolysis
  • Hypoxia (metabolism)
  • Lysophospholipids (metabolism)
  • Naphthalenes (pharmacology)
  • Phospholipases A (metabolism)
  • Phospholipases A2
  • Plasmalogens (metabolism)
  • Pyrones (pharmacology)
  • Thrombin (pharmacology)

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