Chronic insulin treatment amplifies PDGF-induced motility in
differentiated aortic smooth muscle cells by suppressing the
expression and function of PTP1B
Daming Zhuang*, Qinghua Pu*, Bogdan Ceacareanu, Yingzi Chang,
Madhulika Dixit, Aviv Hassid
Department of Physiology
University of Tennessee Health Science Center
Memphis, TN 38163
Mechanisms of enhanced cell motility induced by insulin
Address correspondence to:
Aviv Hassid, PhD
Department of Physiology
University of Tennessee
894 Union Avenue
Memphis, TN 38163
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Articles in PresS. Am J Physiol Heart Circ Physiol (May 2, 2008). doi:10.1152/ajpheart.01105.2007
Copyright © 2008 by the American Physiological Society.
*These authors made equal contribution to this work.
Grants: This work was supported by grants HL63886 and HL72902, from NIH.
Current address for Yingzi Chang:
Department of Pharmacology
A.T. Still University
800 W. Jefferson St.
Kirksville, MO 63501
Current address for Bogdan Ceacareanu:
8315 Trinity Rd
Memphis, TN 38018
Current address for Madhulika Dixit:
Department of Biotechnology
Indian Institute of Technology Madras (IIT Madras)
Chennai 600036, India
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Hyperinsulinemia plays a major role in the pathogenesis of vascular disease.
Restenosis occurs at an accelerated rate in hyperinsulinemia and is dependent on
increased vascular smooth muscle cell movement from media to neointima. PDGF
plays a critical role in mediating neointima formation in models of vascular injury. We
have reported that PDGF increases the levels of protein tyrosine phosphatase PTP1B
and that PTP1B suppresses PDGF-induced motility in cultured cells and that it
attenuates neointima formation in injured carotid arteries. Others have reported that
insulin enhances the mitogenic and motogenic effects of PDGF in cultured smooth
muscle cells and that hyperinsulinemia promotes vascular remodeling. In the present
study, we tested the hypothesis that insulin amplifies PDGF-induced cell motility by
suppressing the expression and function of PTP1B. We found that chronic but not acute
treatment of cells with insulin enhances PDGF-induced motility in differentiated cultured
primary rat aortic smooth muscle cells and that it suppresses PDGF-induced
upregulation of PTP1B protein. Moreover, insulin suppresses PDGF-induced
upregulation of PTP1B mRNA levels, PTP1B enzyme activity and the binding of PTP1B
to the PDGFβ receptor and it enhances PDGF-induced PDGF receptor
phosphotyrosylation. Treatment with insulin induces time-dependent upregulation of PI
3 kinase delta, and activation of Akt, an enzyme downstream of PI 3 kinase. Finally,
inhibition of PI 3 kinase activity, or its function, by pharmacological or genetic means,
rescues PTP1B activity in insulin-treated cells. These observations uncover novel
mechanisms that explain how insulin amplifies the motogenic capacity of the pivotal
growth factor PDGF.
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Vascular pathology; PI 3 kinase delta; Akt; primary culture
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Type 2 diabetes, involving hyperinsulinemia, insulin resistance and hyperglycemia, is
strongly associated with the occurrence of atherosclerosis in experimental models (57).
Restenosis, an event dependent on neointimal enlargement, occurs frequently after
coronary angioplasty, especially in humans manifesting insulin resistance (32).
Moreover, plasma insulin levels in the U.S. population have reportedly increased by
~35% during the last decade (35).
Several studies have reported that chronic hyperinsulinemia, even in absence of
hyperglycemia, constitutes an independent risk factor for cardiovascular disease and
restenosis in humans (2, 11, 52, 56, 62). A recent study found that chronically elevated
insulin levels may be more important for induction of experimental neointima than
elevated glucose levels (26). Indeed, hyperglycemia alone has been reported to
decrease vascular smooth muscle proliferation (9, 51) and neointima formation in
vascular injury (26).
PDGF is thought to be a pivotal mediator of neointimal enlargement that occurs in
experimental vascular injury, on the basis of reports indicating that treatment with PDGF
antagonists, or the use of agents that decrease endogenous PDGF levels, attenuates
neointimal enlargement (15, 16, 34, 38, 61), and that treatment with PDGF enhances
the formation of neointima (28). Moreover, PDGF mRNA levels have been reported to
be increased in human atherosclerotic plaques (58), and the PDGF receptor is
upregulated in vascular injury (1, 44).
PDGF appears to enhance neointima formation by stimulating vascular smooth muscle
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