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

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. 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 -subunits (1(I) and 2(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-1(I) and mature 1(I) expression in cultured medium. IGF-1 infusion in Apoe(-/-) mice increased expression of LARP6 and pro-1(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.