Published online before print October 26, 2006, doi: 10.1161/01.RES.0000251231.16993.88
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 American Heart Association, Inc.
Molecular Medicine |
C-Peptide Induces Vascular Smooth Muscle Cell Proliferation
Involvement of Src-Kinase, Phosphatidylinositol 3-Kinase, and Extracellular Signal-Regulated Kinase 1/2
From the Department of Internal Medicine II, Cardiology (D.W., C.B., P.P., H.B., S.B., R.D., M.G., V.H.), University of Ulm, Germany; Department of Internal Medicine III (S.R.), University of Cologne, Germany; Health Sciences Center (J.S.), Louisiana State University, New Orleans.
Correspondence to Nikolaus Marx, MD, Department of Internal Medicine II, Cardiology, University of Ulm, Robert-Koch-Str. 8, D-89081 Ulm, Germany. E-mail nikolaus.marx{at}uniklinik-ulm.de
Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest a potential causal role of C-peptide in atherogenesis by promoting monocyte and T-lymphocyte recruitment into the vessel wall. The present study examined the effect of C-peptide on vascular smooth muscle cells (VSMCs) proliferation and evaluated intracellular signaling pathways involved. In early arteriosclerotic lesions of diabetic subjects, C-peptide colocalized with VSMCs in the media. In vitro, stimulation of human or rat VSMCs with C-peptide induced cell proliferation in a concentration-dependent manner with a maximal 2.6±0.8-fold induction at 10 nmol/L human C-peptide (P<0.05 compared with unstimulated cells; n=9) and a 1.8±0.2-fold induction at 0.5 nmol/L rat C-peptide (P<0.05 compared with unstimulated cells; n=7), respectively, as shown by [H3]-thymidin incorporation. The proliferative effect of C-peptide on VSMCs was inhibited by Src short interference RNA transfection, PP2, an inhibitor of Src-kinase, LY294002, an inhibitor of PI-3 kinase, and the ERK1/2 inhibitor PD98059. Moreover, C-peptide induced phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2, suggesting that these signaling molecules are involved in C-peptide–induced VSMC proliferation. Finally, C-peptide induced cyclin D1 expression as well as phosphorylation of Rb in VSMCs. Our results demonstrate that C-peptide induces VSMC proliferation through activation of Src- and PI-3 kinase as well as ERK1/2. These data suggest a novel mechanism how C-peptide may contribute to plaque development and restenosis formation in patients with insulin resistance and early type 2 diabetes mellitus.
Key Words: C-peptide • diabetes mellitus • restenosis • smooth muscle cells • proliferation
Related Article:
Circ. Res. 2006 99: 1149-1151.
This article has been cited by other articles:
 |
|
 |
|
  P. Wang, T.-Y. Xu, Y.-F. Guan, D.-F. Su, G.-R. Fan, and C.-Y. Miao Perivascular adipose tissue-derived visfatin is a vascular smooth muscle cell growth factor: role of nicotinamide mononucleotide Cardiovasc Res, February 1, 2009; 81(2): 370 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Langouche, S. Vander Perre, P. J. Wouters, A. D'Hoore, T. K. Hansen, and G. Van den Berghe Effect of Intensive Insulin Therapy on Insulin Sensitivity in the Critically Ill J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3890 - 3897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Bruemmer C-Peptide in Insulin Resistance and Vascular Complications: Teaching an Old Dog New Tricks Circ. Res., November 24, 2006; 99(11): 1149 - 1151. [Full Text] [PDF]
|
|