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

• Published in: The Journal of biological chemistry 2014-03, Vol.289 (11), p.7264-7274
• Main Authors: Blackstock, Christopher D., Higashi, Yusuke, Sukhanov, Sergiy, Shai, Shaw-Yung, Stefanovic, Branko, Tabony, A. Michael, Yoshida, Tadashi, Delafontaine, Patrice
• Format: Article
• Language: English
• Subjects: 5′ Stem-loop; Acheron; Akt; Animals; Aorta - cytology; Atherosclerosis; Atherosclerosis - metabolism; Autoantigens - metabolism; Cells, Cultured; Collagen Type I - metabolism; Collagen Type I, alpha 1 Chain; Fibrillogenesis; Gene Expression Regulation; Humans; Insulin-like Growth Factor (IGF); Insulin-Like Growth Factor I - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular Bases of Disease; Muscle, Smooth - cytology; Mutation; Myocytes, Smooth Muscle - metabolism; Oxidative Stress; Plaque, Atherosclerotic - metabolism; Post-transcriptional; Protein Synthesis; Ribonucleoproteins - metabolism; RNA, Messenger - metabolism; Signal Transduction; SS-B Antigen; Translation; Vascular Smooth Muscle Cells
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.518951

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. Background: The la ribonucleoprotein domain family member 6, LARP6, regulates collagen type 1 mRNA translation. Results: IGF-1 increases LARP6 expression, resulting in increased LARP6-collagen type 1 mRNA complex and collagen synthesis in smooth muscle. Conclusion: IGF-1 enhances collagen fibrillogenesis via induction of LARP6. Significance: This report uncovers a critical mechanism whereby IGF-1 induces a more stable plaque phenotype in atherosclerosis.