Abstract 13854: Micro-RNA Regulation of Collagen Production by Vascular Smooth Muscle Cells Mediated by La Ribonucleoprotein Domain Family Member 6: Potential Mechanisms Underlying Stable Phenotype of Atherosclerotic Plaque by Insulin-like Growth Factor 1
Collagen is a major constituent of the extracellular matrix in atherosclerotic plaques and supports plaque stability. La ribonucleoprotein domain family member 6 (LARP6) is an RNA binding protein, which assists translation of fibrillar collagen, thereby promoting mature collagen deposition. In Apoe-null mice, insulin-like growth factor 1 (IGF1) promoted stable features of plaques by increasing smooth muscle cell (SMC) numbers and mature collagen fibril deposition without increasing plaque burden. To study mechanisms underlying the IGF1’s plaque stabilizing effects, we exposed human aortic SMCs to proatherogenic oxidized LDL (oxLDL) or IGF1 and determined collagen expression levels. OxLDL downregulated collagen (I) by 36.0±3.2% (P<0.05), along with LARP6 (40.9±10.4 % decrease, P<0.05) and procollagen (I) (49.0±8.9 % decrease, P<0.05), which are consistent with decreased translation of procollagen (I) mRNA. IGF1 abolished oxLDL effects, reversing LARP6 and procollagen (I) protein levels, and thus increased collagen (I) to the levels comparable with native LDL-treated control. As we found previously, the IGF1 upregulation of collagen (I) was mediated by enhanced expression of LARP6, however IGF1 did not alter LARP6 mRNA levels, suggesting translational/post-translational mechanisms. Micro RNA regulates translation of mRNAs; in fact, miR-126, miR-744, and miR-1976 target LARP6 mRNA. In human aortic SMCs, oxLDL upregulated miR-1976 by 40.4±0.5 %, implying miR-mediated suppression of LARP6 translation. Intriguingly, IGF1 abrogated the oxLDL upregulation of miR-1976; moreover, IGF1 decreased miR-126 (by 25.0±1.0 %, P<0.05) and miR-744 (by 24.0±0.4 %, P<0.01), further suggesting that downregulation of miRs mediated IGF1 upregulation of LARP6. To evaluate LARP6 expression in human atherosclerotic plaques, atherosclerotic carotid artery sections were stained for LARP6, and it was detected mainly in SMCs in the medial layer and in the plaque fibrous cap, where collagen fibrils are integral components supporting plaque stability. Our findings suggest a novel mechanism of collagen accumulation by miR-dependent LARP6 expression, and provide a basis for a novel therapeutic approach to enhance plaque stability by targeting miR.
Author Disclosures: Y. Higashi: None. S. Danchuk: None. S. Sukhanov: None. C. Blackstock: None. Z. Li: None. P. Snarski: None. P. Delafontaine: None.
- © 2016 by American Heart Association, Inc.