Song Gao1, Michael Wassler2, Lulu Zhang2, Yangxin Li3, Jun Wang3, Yi Zhang4, Harnath Shelat2, Jason Williams2, Yong-Jian Geng5. 1. The Texas Heart Institute at St. Luke's Hospital, Houston, TX, USA; The University of Texas Medical School at Houston, Houston, TX, USA. 2. The University of Texas Medical School at Houston, Houston, TX, USA. 3. The Texas Heart Institute at St. Luke's Hospital, Houston, TX, USA. 4. The Texas Heart Institute at St. Luke's Hospital, Houston, TX, USA; The Affiliated Hospital of Hainan Medical University, Haikou, China. 5. The Texas Heart Institute at St. Luke's Hospital, Houston, TX, USA; The University of Texas Medical School at Houston, Houston, TX, USA. Electronic address: yong-jian.geng@uth.tmc.edu.
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.
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.
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