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 alpha subunits (a1(I) and a2(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 posttranscriptional 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-a1(I) and mature a1(I) expression in cultured medium. IGF-1 infusion in Apoe-/- mice increased expression of LARP6 and pro-a1(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.

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