title: Lysophosphatidylcholine promotes P-selectin expression in platelets and endothelial cells. Possible involvement of protein kinase C activation and its inhibition by nitric oxide donors.
abstract: Lysophosphatidylcholine (LysoPC), an atherogenic lysophospholipid contained in oxidized low-density lipoprotein (LDL), has been shown to stimulate protein kinase C (PKC). Since PKC activators are suggested to elicit rapid P-selectin expression in platelets and endothelial cells, we examined whether LysoPc promotes P-selectin expression in platelets and P-selectin-mediated leukocyte adherence to endothelial cells via a mechanism involving PKC activation. LysoPc, but not phosphatidylcholine (PC), which is a major phospholipid component in native LDL, significantly upregulated P-selectin on cat platelets by flow cytometric analysis. This P-selectin upregulation by LysoPC was significantly attenuated by two PKC inhibitors, 7-hydroxystaurosporine (UCN-01) and N,N,N-trimethylsphingosine, and by two NO donors, CAS1609 and sodium nitroprusside. Submicellar concentrations of LysoPc significantly activated PKC in platelets, and this was inhibited by either UCN-01 or CAS1609. LysoPC, but not PC, significantly increased adherence of autologous cat polymorphonuclear leukocytes to coronary vascular endothelium, which was also markedly attenuated by UCN-01 and by CAS1609. LysoPC induced P-selectin expression on the surface of cat coronary vascular endothelium as assessed by immunohistochemical analysis. These results suggest that LysoPC, an atherogenic lysophospholipid contained in oxidized LDL, rapidly induces P-selectin expression in both platelets and endothelial cells at least partially via PKC activation. Furthermore, NO-generating agents may inhibit P-selectin upregulation by LysoPC. Since P-selectin may play an important role in initiating atherosclerosis, our data provide further insight into the mechanism of early stages of atherogenesis and of NO-mediated inhibition of atherosclerosis.
authors.affiliation: Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107-6799, USA.
authors.forename: T
authors.initials: T
authors.lastname: Murohara
authors.forename: R
authors.initials: R
authors.lastname: Scalia
authors.forename: A M
authors.initials: AM
authors.lastname: Lefer
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D003331:Coronary Vessels / Q000502:physiology; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000166:cytology / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D007150:Immunohistochemistry; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D019007:P-Selectin / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C094475:4-hydroxynethyl-furoxan-3-carboxamide; D008244:Lysophosphatidylcholines; D010069:Oxadiazoles; D019007:P-Selectin; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D011493:Protein Kinase C; D013917:Thrombin; D013755:Tetradecanoylphorbol Acetate