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Activated alpha 2-macroglobulin promotes mitogenesis in rat vascular smooth muscle cells by a mechanism that is independent of growth-factor-carrier activity.

Publication ,  Journal Article
Webb, DJ; Hussaini, IM; Weaver, AM; Atkins, TL; Chu, CT; Pizzo, SV; Owens, GK; Gonias, SL
Published in: Eur J Biochem
December 15, 1995

Vascular smooth muscle cell (vSMC) proliferation is important in atherosclerosis. We previously demonstrated that methylamine-activated alpha 2-macroglobulin (alpha 2M) and transforming growth factor beta 1 (TGF-beta 1) cause a synergistic proliferative response in quiescent rat aortic vSMCs [Stouffer, G. A., La-Marre, J., Gonias, S. L. & Owens, G. K. (1993) J. Biol. Chem. 268, 18,340-18,344]. The first goal of this study was to determine whether the synergy is due to the ability of alpha 2M-methylamine (alpha 2M-MeNH2) to bind TGF-beta 1 and target the growth factor to vSMCs that express the alpha 2M receptor. Receptor-recognized alpha 2M derivatives without TGF-beta 1-binding activity, including ternary alpha 2M-trypsin, an 18-kDa proteolytic fragment of the alpha 2M subunit, and the corresponding recombinant receptor-binding fragment (rRBF) increased vSMC [3H]thymidine incorporation and cell number in a manner similar to alpha 2M-MeNH2. In combination with TGF-beta 1, each alpha 2M derivative caused a synergistic vSMC proliferative response. vSMCs responded comparably when treated with alpha 2M-MeNH2 and TGF-beta 1 simultaneously or in sequence. Furthermore, alpha 2M-MeNH2-TGF-beta 1 complexes increased [3H]thymidine incorporation no more than alpha 2M-MeNH2 alone. These results indicate that TGF-beta 1 binding to alpha 2M is not responsible for the synergistic mitogenic activity. Additional studies were undertaken to determine whether activated alpha 2M independently induces a signal-transduction response in vSMCs. alpha 2M-MeNH2 and rRBF caused a rapid, transient increase in vSMC inositol 1,4,5-trisphosphate. This response was pertussis-toxin insensitive. Receptor-associated protein (RAP; 170 nmol/L) inhibited 91-95% of the specific binding of 125I-alpha 2M-MeNH2 and 125I-rRBF to vSMC; however, RAP did not affect the inositol 1,4,5-trisphosphate response or the mitogenic response. These studies suggest that vSMCs express a receptor, other than low-density-lipoprotein-receptor-related protein, that transduces a signal in response to activated alpha 2M. This receptor may mediate the mitogenic activity of alpha 2M in vSMC culture.

Duke Scholars

Published In

Eur J Biochem

DOI

ISSN

0014-2956

Publication Date

December 15, 1995

Volume

234

Issue

3

Start / End Page

714 / 722

Location

England

Related Subject Headings

  • alpha-Macroglobulins
  • Virulence Factors, Bordetella
  • Trypsin
  • Transforming Growth Factor beta
  • Signal Transduction
  • Recombinant Proteins
  • Receptors, Immunologic
  • Rats, Sprague-Dawley
  • Rats
  • Protein Binding
 

Citation

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Webb, D. J., Hussaini, I. M., Weaver, A. M., Atkins, T. L., Chu, C. T., Pizzo, S. V., … Gonias, S. L. (1995). Activated alpha 2-macroglobulin promotes mitogenesis in rat vascular smooth muscle cells by a mechanism that is independent of growth-factor-carrier activity. Eur J Biochem, 234(3), 714–722. https://doi.org/10.1111/j.1432-1033.1995.714_a.x
Webb, D. J., I. M. Hussaini, A. M. Weaver, T. L. Atkins, C. T. Chu, S. V. Pizzo, G. K. Owens, and S. L. Gonias. “Activated alpha 2-macroglobulin promotes mitogenesis in rat vascular smooth muscle cells by a mechanism that is independent of growth-factor-carrier activity.Eur J Biochem 234, no. 3 (December 15, 1995): 714–22. https://doi.org/10.1111/j.1432-1033.1995.714_a.x.
Webb DJ, Hussaini IM, Weaver AM, Atkins TL, Chu CT, Pizzo SV, et al. Activated alpha 2-macroglobulin promotes mitogenesis in rat vascular smooth muscle cells by a mechanism that is independent of growth-factor-carrier activity. Eur J Biochem. 1995 Dec 15;234(3):714–22.
Webb, D. J., et al. “Activated alpha 2-macroglobulin promotes mitogenesis in rat vascular smooth muscle cells by a mechanism that is independent of growth-factor-carrier activity.Eur J Biochem, vol. 234, no. 3, Dec. 1995, pp. 714–22. Pubmed, doi:10.1111/j.1432-1033.1995.714_a.x.
Webb DJ, Hussaini IM, Weaver AM, Atkins TL, Chu CT, Pizzo SV, Owens GK, Gonias SL. Activated alpha 2-macroglobulin promotes mitogenesis in rat vascular smooth muscle cells by a mechanism that is independent of growth-factor-carrier activity. Eur J Biochem. 1995 Dec 15;234(3):714–722.

Published In

Eur J Biochem

DOI

ISSN

0014-2956

Publication Date

December 15, 1995

Volume

234

Issue

3

Start / End Page

714 / 722

Location

England

Related Subject Headings

  • alpha-Macroglobulins
  • Virulence Factors, Bordetella
  • Trypsin
  • Transforming Growth Factor beta
  • Signal Transduction
  • Recombinant Proteins
  • Receptors, Immunologic
  • Rats, Sprague-Dawley
  • Rats
  • Protein Binding