MicroRNA-133a regulates insulin-like growth factor-1 receptor expression and vascular smooth muscle cell proliferation in murine atherosclerosis

Abstract

Objective MicroRNA-133a (miR-133a) and insulin-like growth factor-1 (IGF-1) are two different molecules known to regulate cardiovascular cell proliferation. This study tested whether miR-133a affects expression of IGF-1 receptor (IGF-1R) and proliferation of IGF-1-stimulated vascular smooth muscle cells (VSMC) in a murine model of atherosclerosis. Methods and Results Expression of IGF-1R was analyzed by immuno-fluorescence and immuno-blotting, and miR-133a by qRT-PCR in the aortas of wild-type C57BL/6J (WT) and apolipoprotein-E deficient (ApoE−/−) mice. Compared to those in WT aortas, the IGF-1R and miR-133a levels were lower in ApoE−/− aortas. ApoE−/− VSMC grew slower than WT cells in the cultures with IGF-1-containing medium. MiR-133a-specific inhibitor decreased miR-133a, IGF-1R expression, IGF-1-stimulated VSMC growth in lipoprotein-deficient media. By contrast, miR-133a precursor increased IGF-1R levels and promoted IGF-1-induced VSMC proliferation. In the luciferase-IGF-1R 3’UTR reporter system, the reporter luciferase activity was not inhibited in VSMC with miR-133a overexpression. IGF-1R mRNA half-life in ApoE−/− VSMC was shorter than that in WT VSMC. MiR-133a inhibitor reduced but precursor increased the mRNA half-life, although the effects appeared less striking in ApoE−/− VSMC than in WT cells. Conclusion MiR-133a serves as a stimulatory factor for IGF-1R expression through prolonging IGF-1R mRNA half-life. In atherosclerosis induced by ApoE deficiency, reduced miR-133a expression is associated with lower IGF-1R levels and suppressive VSMC growth. Administration of miR-133a precursor may potentiate IGF-1 stimulated VSMC survival and growth.

MiR-378 Promotes the Migration of Liver Cancer Cells by Down-Regulating Fus Expression

“…miRNAs pair with the messages of protein-coding genes to direct post-transcriptional repression [3] and target mRNAs based on sequence complementarity with target 3′-untranslated regions (3′-UTRs), leading to translational repression and/or to mRNA cleavage [4]. miRNAs are involved in cell differentiation [5], apoptosis [6], cell proliferation [7,8], division [9], protein secretion [10], immune regulation [11], viral infection [12], cancer development [13,14], invasion [15,16], tissue morphogenesis and growth [17,18], angiogenesis [19,20] and metastasis [21]. The largest functional group of miRNAs are those miRNAs involved in cancer development, and among these, some have been reported to function as oncogenic miRNAs or tumor suppressors, whereas others exert diverse functions [22].…”

Functions of miR-1 and miR-133a during the postnatal development of masseter and gastrocnemius muscles

“…More importantly, miR-133 targeting Sp-1, which is needed for Klf4 activation to down-regulate myocardin, prevents myocardin repression of VSMC proliferation on PDGF-BB stimulation in vitro [17]. By contrast, Gao et al also reported that miR-133a enhances VSMC proliferation by stimulating IGF-1R expression, in a murine model of atherosclerosis [18].…”

“…However, miR-133 may play different roles in different types of cells. For example, it appears to have both positive and negative effects on proliferation, depending on the type of muscle cell, such as in C2C12 cells or balloon-injured vascular cells [17,18].…”

“…On the other hand, in vascular smooth muscle cells (VSMCs), miR-133 inhibitor administration did not affect rat VSMC proliferation, while miR-133 overexpression triggered cell phenotypical transformation and vascular muscle layer remodeling [17]. By contrast, Gao et al reported that miR-133a enhanced VSMC proliferation by stimulating IGF-1R expression in a murine model of atherosclerosis [18]. These previous studies of VSMCs suggest that miR-133 appears to have both positive and negative effects on proliferation, depending on the type of muscle cell, such as in C2C12 myoblasts or balloon-injured vascular cells.…”

MicroRNA-433 inhibits cell proliferation in hepatocellular carcinoma by targeting p21 activated kinase (PAK4)

“…For example, it was recently reported that miR-133 inhibitor did not significantly affect rat VSMC proliferation, while miRNA-133 contributed to the cell phenotypical transformation and vascular muscle layer remodeling [27]. Furthermore, another study showed that miRNA-133a expression enhanced VSMC proliferation through promoting IGF-1R expression [28]. These findings reflect the complexity of the functions of miRNAs in regulating cell growth and proliferation.…”