Glucose regulation of thrombospondin and its role in the modulation of smooth muscle cell proliferation.
Smooth muscle cells (SMC) maintained in high glucose are more responsive to IGF-I than those in normal glucose. There is significantly more thrombospondin-1 (TSP-1) in extracellular matrix surrounding SMC grown in 25 mM glucose. In this study we investigated 1) the mechanism by which glucose regulates TSP-1 levels and 2) the mechanism by which TS-1 enhances IGF-I signaling. The addition of TSP-1 to primary SMC was sufficient to enhance IGF-I responsiveness in normal glucose. Reducing TSP-1 protein levels inhibited IGF-I signaling in SMC maintained in high glucose. We determined that TSP-1 protected IAP/CD47 from cleavage and thereby facilitated its association with SHP substrate-1 (SHPS-1). We have shown previously that the hyperglycemia induced protection of IAP from cleavage is an important component of the ability of hyperglycemia to enhance IGF-I signaling. Furthermore we determined that TSP-1 also enhanced phosphorylation of the beta3 subunit of the alphaVbeta3 integrin, another molecular event that we have shown are critical for SMC response to IGF-I in high glucose. Our studies also revealed that the difference in the amount of TSP-1 in the two different glucose conditions was due, at least in part, to a difference in the cellular uptake and degradation of TSP-1.
Maile
Laura A
LA
Division of Endocrinology, University of North Carolina, CB# 7170, 5030 Burnett Womack, Chapel Hill, NC 27599-7170, USA. laura_maile@med.unc.edu
Allen
Lee B
LB
Hanzaker
Christopher F
CF
Gollahon
Katherine A
KA
Dunbar
Paul
P
Clemmons
David R
DR
D000818:Animals; D051928:CD47 Antigen / Q000378:metabolism; D049109:Cell Proliferation; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006943:Hyperglycemia / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D013552:Swine; D019700:Thrombospondin 1 / Q000378:metabolism* / Q000494:pharmacology
D051928:CD47 Antigen; D039302:Integrin alphaVbeta3; D019700:Thrombospondin 1; D007334:Insulin-Like Growth Factor I; D005947:Glucose