© 1995 American Heart Association, Inc.
Articles |
Differentiation of Vascular Smooth Muscle Cells and the Regulation of Protein Kinase C-
From the Department of Medicine and Nephrology, Steglitz University Hospital, and the Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, Rudolf Virchow University Hospitals, Free University of Berlin (Germany).
Correspondence to Hermann Haller, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, Germany.
Abstract Dedifferentiation and proliferation of vascular
smooth muscle cells (VSMCs) are important features of atherosclerosis.
The molecular mechanisms are largely unclear; however, protein kinase C
(PKC) is a key enzyme in the intracellular signaling pathways that
mediate this process. We studied the activity and immunoreactivity of
PKC-
in primary cultures of VSMCs from rat aortas under different
conditions of growth and differentiation. PKC- was determined under
the following conditions: (1) during the growth phase and after
confluence of cultured (passages 1 through 3) VSMCs, (2) before and
after induction of differentiation in VSMCs by retinoic acid, and (3)
in primary cultures of VSMCs from spontaneously hypertensive rats (SHR)
and Wistar-Kyoto (WKY) rats during early passages. PKC activity was
measured by in vitro substrate phosphorylation. PKC-
immunoreactivity was assessed by Western blot using specific polyclonal
antibodies and by immunostaining with confocal microscopy. Cell
proliferation was measured by direct count. The cell phenotype was
characterized by immunostaining and Western blot for -actin and
desmin. PKC- expression and PKC activity during VSMC growth showed a
decrease during rapid growth and an increase in confluent cells. This
pattern was associated with the respective changes in cell
differentiation. Retinoic acid induced an increase in PKC-
expression together with a more differentiated phenotype. Subcultured,
rapidly growing VSMCs from SHR showed a decreased PKC- expression
compared with cells from WKY rats. To establish cause and effect, we
next microinjected either PKC- or inactivated material directly into
dedifferentiated cells. We found that cells injected with active
PKC- expressed increased amounts of actin compared with control
cells. We identified a close correlation between PKC- and actin
immunofluorescence. We conclude that PKC- is downregulated in
rapidly growing VSMCs. Our findings demonstrate an inverse association
between PKC- expression and VSMC differentiation. They suggest a
role for downregulation of PKC- in the proliferative response of
these cells.
Key Words: protein kinase C • protein kinase C isoforms • vascular smooth muscle cells • spontaneously hypertensive rats • cell proliferation
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