UCN-01, a Protein Kinase C Inhibitor, Inhibits Endothelial Cell Proliferation and Angiogenic Hypoxic Response

1998 ◽  
Vol 18 (4) ◽  
pp. 209-218 ◽  
Author(s):  
Erwin A. Kruger ◽  
Mikhail V. Blagosklonny ◽  
Shannon C. Dixon ◽  
William D. Figg
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Endothelial Cell ◽  
Protein Kinase ◽  
Endothelial Cell Proliferation ◽  
Hypoxic Response ◽  
Kinase C ◽  
Protein Kinase C Inhibitor

scholarly journals Protein kinase C activators suppress stimulation of capillary endothelial cell growth by angiogenic endothelial mitogens.

1987 ◽  
Vol 104 (3) ◽  
pp. 679-687 ◽  
Author(s):  
S R Doctrow ◽  
J Folkman
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Protein Kinase C ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Protein Kinase ◽  
Cell Growth ◽  
Human Hepatoma ◽  
Kinase C ◽  
Protein Kinase C Activators

The intracellular events regulating endothelial cell proliferation and organization into formalized capillaries are not known. We report that the protein kinase C activator beta-phorbol 12,13-dibutyrate (PDBu) suppresses bovine capillary endothelial (BCE) cell proliferation (K50 = 6 +/- 4 nM) and DNA synthesis in response to human hepatoma-derived growth factor, an angiogenic endothelial mitogen. In contrast, PDBu has no effect on the proliferation of bovine aortic endothelial cells and is mitogenic for bovine aortic smooth muscle and BALB/c 3T3 cells. Several observations indicate that the inhibition of human hepatoma-derived growth factor-stimulated BCE cell growth by PDBu is mediated through protein kinase C. Different phorbol compounds inhibit BCE cell growth according to their potencies as protein kinase C activators (12-O-tetradecanoylphorbol 13-acetate greater than PDBu much greater than beta-phorbol 12,13-diacetate much much greater than beta-phorbol; alpha-phorbol 12,13-dibutyrate; alpha-phorbol 12,13-didecanoate). PDBu binds to a single class of specific, saturable sites on the BCE cell with an apparent Kd of 8 nM, in agreement with reported affinities of PDBu for protein kinase C in other systems. Specific binding of PDBu to BCE cells is displaced by sn-1,2-dioctanoylglycerol, a protein kinase C activator and an analog of the putative second messenger activating this kinase in vivo. The weak protein kinase C activator, sn-1,2-dibutyrylglycerol, does not affect PDBu binding. A cytosolic extract from BCE cells contains a calcium/phosphatidylserine-dependent protein kinase that is activated by sn-1,2-dioctanoylglycerol and PDBu, but not by beta-phorbol. These findings indicate that protein kinase C activation can cause capillary endothelial cells to become desensitized to angiogenic endothelial mitogens. This intracellular regulatory mechanism might be invoked during certain phases of angiogenesis, for example when proliferating endothelial cells become differentiated to organize into nongrowing tubes.

Possible roles of neuropeptide Y Y3-receptor subtype in rat aortic endothelial cell proliferation under hypoxia, and its specific signal transduction

2007 ◽  
Vol 293 (2) ◽  
pp. H959-H967 ◽  
Author(s):  
Zhi-Yong Chen ◽  
Guo-Gang Feng ◽  
Kimitoshi Nishiwaki ◽  
Yasuhiro Shimada ◽  
Yoshihiro Fujiwara ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Neuropeptide Y ◽  
Endothelial Cell Proliferation ◽  
Phosphatidylinositol 3 Kinase ◽  
Large Molecules ◽  
Kinase C ◽  
Phosphatidylinositol 3 ◽  
Aortic Endothelial

The present study was undertaken to determine whether neuropeptide Y (NPY) induces proliferation of rat aortic endothelial cells (RAECs). Since NPY increased the permeability of RAEC monolayers to large molecules via the NPY Y3 receptor, RAEC proliferation has been evaluated in terms of NPY-receptor subtypes and also intracellular mechanisms. RAECs were incubated with gases containing 20, 15, or 10% O2 and a certain amount of N2, depending on the O2 content in 5% CO2 incubators. NPY (10−9–10−6 M) increased the RAEC numbers under hypoxic conditions, such as 15 or 10% O2. Peptide YY elicited no proliferative effect on RAEC, and NPY-(18-36) inhibited the NPY-induced increase in cell number, suggesting that NPY increases the RAEC count through the NPY Y3 receptor. Pertussis toxin, U-73122, GF-109203X, myristorylated autocamtide-2-related inhibitory peptide, and wortmannin inhibited the NPY-induced proliferation of RAEC concentration dependently. DY9760e little affected the proliferation caused by NPY. ML-9 and imatinib actually enhanced the NPY-induced proliferation of cells. These results indicated that the NPY Y3 receptor is coupled with Gi protein, and that NPY-induced increases in RAEC proliferation are mediated by phospholipase C-protein kinase C and/or phosphatidylinositol 3-kinase pathways. In intracellular Ca2+-calmodulin-dependent pathways, calmodulin-dependent protein kinase II partly participates in the NPY-induced cell proliferation. Regarding the previously reported effect of NPY on the permeability of RAEC monolayers to large molecules, it is probable that protein kinase C and phosphatidylinositol 3-kinase pathways are activated for both permeability and cell proliferation induced by NPY under hypoxia, relevant to new insights into the roles of NPY in ischemia-hypoxia.

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