Insulin-like growth factor-1 increases synthesis of collagen type I via induction of the mRNA-binding protein LARP6 expression and binding to the 5' stem-loop of COL1a1 and COL1a2 mRNA.
Collagen content in atherosclerotic plaque is a hallmark of plaque stability. Our earlier studies showed that insulin-like growth factor-1 (IGF-1) increases collagen content in atherosclerotic plaques of Apoe(-/-) mice. To identify mechanisms we investigated the effect of IGF-1 on the la ribonucleoprotein domain family member 6 (LARP6). LARP6 binds a stem-loop motif in the 5'-UTR of the mRNAs encoding the collagen type I α-subunits (α1(I) and α2(I)), and coordinates their translation into the heterotrimeric collagen type I molecule. In human aortic smooth muscle cells (SMCs), IGF-1 rapidly increased LARP6 expression and the rate of collagen synthesis and extracellular accumulation. IGF-1 increased both LARP6 and collagen type I expression via a post-transcriptional and translation-dependent mechanism involving PI3K/Akt/p70S6k-signaling. Immunoprecipitation of LARP6, followed by qPCR indicated that IGF-1 increased the level of COL1a1 and COL1a2 mRNA bound to LARP6. Mutation of the 5' stem-loop of Col1a1 mRNA, which inhibits binding of LARP6, abolished the ability of IGF-1 to increase synthesis of collagen type I. Furthermore, overexpression of a 5' stem-loop RNA molecular decoy that sequesters LARP6, prevented the ability of IGF-1 to increase pro-α1(I) and mature α1(I) expression in cultured medium. IGF-1 infusion in Apoe(-/-) mice increased expression of LARP6 and pro-α1(I) in aortic lysates, and SMC-specific IGF-1-overexpression robustly increased collagen fibrillogenesis in atherosclerotic plaque. In conclusion, we identify LARP6 as a critical mediator by which IGF-1 augments synthesis of collagen type I in vascular smooth muscle, which may play an important role in promoting atherosclerotic plaque stability.
From the Heart and Vascular Institute, and Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112 and.
Christopher D
CD
Blackstock
Yusuke
Y
Higashi
Sergiy
S
Sukhanov
Shaw-Yung
SY
Shai
Branko
B
Stefanovic
A Michael
AM
Tabony
Tadashi
T
Yoshida
Patrice
P
Delafontaine
D000818:Animals; D001011:Aorta / Q000166:cytology; D050197:Atherosclerosis / Q000378:metabolism; D001324:Autoantigens / Q000378:metabolism*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism*; D000090602:Collagen Type I, alpha 1 Chain; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000166:cytology; D009154:Mutation; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism*; D015398:Signal Transduction; D000097585:SS-B Antigen
D001324:Autoantigens; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D007334:Insulin-Like Growth Factor I; D012333:RNA, Messenger; D012261:Ribonucleoproteins; D000097585:SS-B Antigen; C583557:IGF1 protein, human; C519530:insulin-like growth factor-1, mouse
5′ Stem-loop; Acheron; Akt; Atherosclerosis; Fibrillogenesis; Insulin-like Growth Factor (IGF); Post-transcriptional; Protein Synthesis; Translation; Vascular Smooth Muscle Cells