© 1995 American Heart Association, Inc.
Articles |
Requirement for Protein Kinase C Activation in Basic Fibroblast Growth Factor–Induced Human Endothelial Cell Proliferation
From the Departments of Surgery (Division of Vascular Surgery) (K.C.K., S.M., S.M.) and Medicine (Cardiovascular Division) (E.O.H., J.D.C., J.A.W.) and the Harvard Thorndike Laboratories and Charles A. Dana Research Institute (E.O.H., J.D.C., J.A.W.), Beth Israel Hospital, Harvard Medical School, Boston, Mass.
Correspondence to K. Craig Kent, MD, Division of Vascular Surgery, Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215.
Abstract The intracellular signaling mechanisms that mediate
basic fibroblast growth factor (bFGF)–induced angiogenesis have not
been fully identified. In particular, whether activation of the
intracellular enzyme protein kinase C (PKC) is necessary or sufficient
for bFGF-induced mitogenesis of human endothelial cells
is not clear. Accordingly, the effect of bFGF stimulation on the
Ca2+ increase and PKC activity of normal human
endothelial cells (HEC) was studied, as was the effect
of inhibition of PKC and the distribution of PKC isoenzymes in these
cells. The addition of bFGF to cultured HEC increased overall PKC
activity in the absence of an increase in intracellular
Ca2+ and markedly stimulated their proliferation, as
did the addition of PKC-activating phorbol esters. bFGF-induced
proliferation was prevented by the PKC inhibitors
chelerythrine and H-7 and by downregulation of PKC after prolonged
incubation with phorbol esters. In contrast, these
inhibitors did not prevent HEC proliferation induced by
epidermal growth factor. Because of the failure of bFGF to increase
Ca2+, we determined whether bFGF-induced
proliferation could be mediated by novel or atypical PKC isoenzymes
(which are not regulated by Ca2+). Investigation of
the isoenzyme distribution of confluent and subconfluent HEC by
immunoblotting, Northern transfer analysis, and polymerase
chain reaction of reverse-transcribed RNA revealed the presence of
several novel and atypical isoenzymes (PKC-
, -
, -
, and -
)
as well as small amounts of the conventional
(Ca2+-regulated) isoenzymes PKC-
and -ß.
Activation of PKC by bFGF, in the absence of an increase in
intracellular Ca2+, suggests that one or more
of these Ca2+-independent PKC isoenzymes are both
necessary and sufficient for HEC proliferation after bFGF.
Key Words: protein kinase C • endothelial cell • growth factors • proliferation • isoenzymes • signal transduction
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