Hyperglycemia upregulates translation of the fibroblast growth factor 2 mRNA in mouse aorta via internal ribosome entry site.
Fibroblast growth factor 2 (FGF-2) is normally synthesized at low levels but is elevated in various pathophysiological conditions including diabetes-associated vascular diseases. FGF-2 expression is regulated translationally through an internal ribosome entry site (IRES) located in its mRNA, which allows a nonclassical cap-independent translation. We addressed the pathophysiological regulation of the IRES in vivo by using a streptozotocin-induced hyperglycemic model known to suppress markedly overall translation. Evaluation of FGF-2 IRES-dependent translation was performed with transgenic mice expressing dual luciferase bicistronic mRNA containing the FGF-2 IRES. FGF-2 IRES-dependent reporter activity increased 240% of control in the diabetic aorta although the reporter mRNA levels significantly decreased. Expression of endogenous FGF-2 protein in the aorta closely correlated with the IRES activity but not with FGF-2 mRNA levels. Moreover, the biosynthesis of endogenous FGF-2 protein was stimulated in an IRES-dependent manner by high glucose that significantly suppressed global protein synthesis in aortic smooth muscle cells from the transgenic mice. These results suggest that IRES-dependent translational regulation could play a pathological role in FGF-2 expression in vivo, especially in the cardiovascular consequences of diabetes.
Institut National de la Santé et de la Recherche Médicale U589, Hormones, Facteurs de Croissance et Physiopathologie Vasculaire, Institut Louis Bugnard IFR31, Hôpital Rangueil, Toulouse, France.
Shigetada
S
Teshima-Kondo
Kazumi
K
Kondo
Leonel
L
Prado-Lourenco
Irma Gabriela
IG
Gonzalez-Herrera
Kazuhito
K
Rokutan
Francis
F
Bayard
Jean-François
JF
Arnal
Anne-Catherine
AC
Prats
D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001665:Binding Sites; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics*; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000235:genetics*; D051379:Mice; D009928:Organ Specificity; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D015854:Up-Regulation / Q000187:drug effects
D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D005947:Glucose