Hypoxia-induced miR-1260b regulates vascular smooth muscle cell proliferation by targeting GDF11
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초록
Vascular smooth muscle cells (VSMCs) are a unique cell type that has unusual plasticity controlled by environmental stimuli. As an abnormal increase of VSMC proliferation is associated with various vascular diseases, tight regulation of VSMC phenotypes is essential for maintaining vascular homeostasis. Hypoxia is one environmental stress that stimulates VSMC proliferation. Emerging evidence has indicated that microRNAs (miRNAs) are critical regulators in the hypoxic responses of VSMCs. Therefore, we previously investigated miRNAs modulated by hypoxia in VSMCs and found that miR-1260b is one of the most upregulated miRNAs under hypoxia. However, the mechanism that underlies the regulation of VSMCs via miR-1260b in response to hypoxia has not been explored. Here we demonstrated that hypoxia-induced miR-1260b promotes VSMC proliferation. We also identified growth differentiation factor 11 (GDF11), a member of the TGF- superfamily, as a novel target of miR-1260b. miR-1260b directly targets the 3’UTR of GDF11. Downregulation of GDF11 inhibited Smad signaling and consequently enhanced the proliferation of VSMCs. Our findings suggest that miR-1260b-mediated GDF11- Smad-dependent signaling is an essential regulatory mechanism in the proliferation of VSMCs, and this axis is modulated by hypoxia to promote abnormal VSMC proliferation. Therefore, our study unveils a novel function of miR-1260b in the pathological proliferation of VSMCs under hypoxia.
Abstract
Vascular smooth muscle cells (VSMCs) are a unique cell type that has unusual plasticity controlled by environmental stimuli. As an abnormal increase of VSMC proliferation is associated with various vascular diseases, tight regulation of VSMC phenotypes is essential for maintaining vascular homeostasis. Hypoxia is one environmental stress that stimulates VSMC proliferation. Emerging evidence has indicated that microRNAs (miRNAs) are critical regulators in the hypoxic responses of VSMCs. Therefore, we previously investigated miRNAs modulated by hypoxia in VSMCs and found that miR-1260b is one of the most upregulated miRNAs under hypoxia. However, the mechanism that underlies the regulation of VSMCs via miR-1260b in response to hypoxia has not been explored. Here we demonstrated that hypoxia-induced miR-1260b promotes VSMC proliferation. We also identified growth differentiation factor 11 (GDF11), a member of the TGF- superfamily, as a novel target of miR-1260b. miR-1260b directly targets the 3’UTR of GDF11. Downregulation of GDF11 inhibited Smad signaling and consequently enhanced the proliferation of VSMCs. Our findings suggest that miR-1260b-mediated GDF11- Smad-dependent signaling is an essential regulatory mechanism in the proliferation of VSMCs, and this axis is modulated by hypoxia to promote abnormal VSMC proliferation. Therefore, our study unveils a novel function of miR-1260b in the pathological proliferation of VSMCs under hypoxia.
참고문헌 (30)
- Owens GK, "Molecular regulation of vascular smooth muscle cell differentiation in development and disease", Physiol Rev, 84, pp.767~801 (2004)
- Owens GK, "Regulation of differentiation of vascular smooth muscle cells", Physiol Rev, 75, pp.487~517 (1995)
- Lagna G, "Control of phenotypic plasticity of smooth muscle cells by bone morphogenetic protein signaling through the myocardin-related transcription factors", J Biol Chem, 282, pp.37244~37255 (2007)
- ten Dijke P, "Extracellular control of TGFbeta signalling in vascular development and disease. Nature reviews", Mol Cell Biol, 8, pp.857~869 (2007)
- Semenza GL, "Life with oxygen", Science, 318, pp.62~64 (2007)
- Stenmark KR, "Hypoxiainduced pulmonary vascular remodeling : cellular and molecular mechanisms", Circ Res, 99, pp.675~691 (2006)
- Semenza GL, "Hypoxia-inducible factors in physiology and medicine", Cell, 148, pp.399~408 (2012)
- Wang GL, "Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension", Proc Natl Acad Sci U S A, 92, pp.5510~5514 (1995)
- Ivan M, "Hypoxia response and microRNAs : no longer two separate worlds", J Cell Mol Med, 12, pp.1426~1431 (2008)
- Kang H, "MicroRNA regulation of smooth muscle gene expression and phenotype", Curr Opi Hemato, 19, pp.224~231 (2012)
- Lee J, "miR-92b-3p-TSC1 axis is critical for mTOR signaling-mediated vascular smooth muscle cell proliferation induced by hypoxia", Cell Death Differ, 26, pp.1782~1795 (2018)
- Hirata H, "Genistein downregulates onco-miR-1260b and inhibits Wnt-signalling in renal cancer cells", Br J Can, 108, pp.2070~2078 (2013)
- Li X, "miR-1260b promotes cell migration and invasion of hepatocellular carcinoma by targeting the regulator of G-protein signaling 22", Biotech Lett, 40, pp.57~62 (2018)
- Xu L, "MiR-1260b promotes the migration and invasion in non-small cell lung cancer via targeting PTPRK", Pathol Res Prac, 214, pp.776~783 (2018)
- Kim J, "GDF11 controls the timing of progenitor cell competence in developing retina", Science, 308, pp.1927~1930 (2005)
- Nakashima M, "Induction of dental pulp stem cell differentiation into odontoblasts by electroporation-mediated gene delivery of growth", differentiation factor 11(Gdf11), 2002, pp.9, 814~818
- Wu HH, "Autoregulation of neurogenesis by GDF11", Neuron, 37, pp.197~207 (2003)
- McPherron AC, "Regulation of anterior", posterior patterning of the axial skeleton by growth, Nat Genetics, pp.1999, 22[DOI]
- Andersson O, "Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anteriorposterior axis", EMBO Rep, 7, pp.831~837 (2006)
- Oh SP, "Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning", Gene Dev, 16, pp.2749~2754 (2002)
- Gaunt SJ, "Direct activation of a mouse Hoxd11 axial expression enhancer by Gdf11", Smad signalling, 2013, pp.383, 52~60
- Hannan NR, "BMP-11 and myostatin support undifferentiated growth of human embryonic stem cells in feeder-free cultures", Clon Stem Cells, 11, pp.427~435 (2009)
- Suragani RN, "Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis", Nat Med, 20, pp.408~414 (2014)
- Williams G, "Transcriptional basis for the inhibition of neural stem cell proliferation and migration by the TGFbeta-family member GDF11", PLoS One, 8, pp.e78478~ (2013)
- Tang F, "Reduced expression of growth differentiation factor 11 promoted the progression of chronic obstructive pulmonary disease by activating the AKT signaling pathway", Biomed Pharmacother, 103, pp.691~698 (2018)
- Fan X, "The Growth Differentiation Factor 11(GDF11)and Myostatin(MSTN)in tissue specific aging", Mech Age Devel, 164, pp.108~112 (2017)
- Poggioli T, "Circulating Growth Differentiation Factor 11", 8 Levels Decline With Age, 2016, pp.118, 29~37
- Davis BN, "SMAD proteins control DROSHA-mediated microRNA maturation", Nature, 454, pp.56~61 (2008)
- Kang H, "Bone morphogenetic protein 4 promotes vascular smooth muscle contractility by activating microRNA-21(miR-21), which down-regulates expression of family of dedicator of cytokinesis(DOCK)proteins", J Biol Chem, 287, pp.3976~3986 (2012)
- Kang H, "Inhibition of microRNA-302(miR-302)by bone morphogenetic protein 4(BMP4)facilitates the BMP signaling pathway", J Biol Chem, 287, pp.38656~38664 (2012)