HDAC6 Regulates the MRTF-A/SRF Axis and Vascular Smooth Muscle Cell Plasticity
| العنوان: | HDAC6 Regulates the MRTF-A/SRF Axis and Vascular Smooth Muscle Cell Plasticity |
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| المؤلفون: | Mengxue Zhang, Go Urabe, Christopher Little, Lian-Wang Guo, Yitao Huang, Alycia Kent, Bowen Wang, K. Craig Kent |
| المصدر: | JACC: Basic to Translational Science JACC: Basic to Translational Science, Vol 3, Iss 6, Pp 782-795 (2018) |
| بيانات النشر: | Elsevier, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Neointima, lcsh:Diseases of the circulatory (Cardiovascular) system, EEL, external elastic lamina, Vascular smooth muscle, Cell, IgG, immunoglobulin G, HDAC, histone deacetylase, IEL, internal elastic lamina, 030204 cardiovascular system & hematology, DMEM, Dulbecco’s modified Eagle’s medium, 03 medical and health sciences, PRECLINICAL RESEARCH, IH, intimal hyperplasia, 0302 clinical medicine, DNA, deoxyribonucleic acid, FBS, fetal bovine serum, siRNA, small interfering ribonucleic acid, Cell Plasticity, medicine, TSA, trichostatin A, Gene silencing, Transcription factor, TNF, tumor necrosis factor, biology, Chemistry, dedifferentiation, PDGF-BB, platelet-derived growth factor-BB, HDAC6, SRF, serum response factor, Cell biology, MMP, matrix metalloproteinase, SMC, vascular smooth muscle cell, 030104 developmental biology, medicine.anatomical_structure, Histone, MRTF-A, lcsh:RC666-701, embryonic structures, MRTF-A, myocardin-related transcription factor A, cardiovascular system, biology.protein, SMA, smooth muscle actin, SRF, vascular smooth muscle cell, SMHC, smooth muscle myosin heavy chain, Cardiology and Cardiovascular Medicine |
| الوصف: | Visual Abstract Highlights • Distinct from other histone deacetylases, HDAC6 primarily resides in the cytosol. • Unexpectedly, HDAC6-selective inhibition (or silencing) enhances the nuclear activity of SRF. • HDAC6 inhibition elevates acetylation and protein levels of myocardin-related transcription factor A, a cytoplasmic-nuclear shuttling co-activator of SRF. Myocardin-related transcription factor A/SRF are known to critically regulate vascular smooth muscle cell phenotypic stability. • HDAC6 inhibition prevents smooth muscle cell dedifferentiation in vitro and reduces neointima and restenosis in vivo. Summary Cellular plasticity is fundamental in biology and disease. Vascular smooth muscle cell (SMC) dedifferentiation (loss of contractile proteins) initiates and perpetrates vascular pathologies such as restenosis. Contractile gene expression is governed by the master transcription factor, serum response factor (SRF). Unlike other histone deacetylases, histone deacetylase 6 (HDAC6) primarily resides in the cytosol. Whether HDAC6 regulates SRF nuclear activity was previously unknown in any cell type. This study found that selective inhibition of HDAC6 with tubastatin A preserved the contractile protein (alpha-smooth muscle actin) that was otherwise diminished by platelet-derived growth factor-BB. Tubastatin A also enhanced SRF transcriptional (luciferase) activity, and this effect was confirmed by HDAC6 knockdown. Interestingly, HDAC6 inhibition increased acetylation and total protein of myocardin-related transcription factor A (MRTF-A), a transcription co-activator known to translocate from the cytosol to the nucleus, thereby activating SRF. Consistently, HDAC6 co-immunoprecipitated with MRTF-A. In vivo studies showed that tubastatin A treatment of injured rat carotid arteries mitigated neointimal lesion, which is known to be formed largely by dedifferentiated SMCs. This report is the first to show HDAC6 regulation of the MRTF-A/SRF axis and SMC plasticity, thus opening a new perspective for interventions of vascular pathologies. |
| اللغة: | English |
| تدمد: | 2452-302X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b88948908b31bd909f037f62bf67192cTest http://europepmc.org/articles/PMC6314972Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b88948908b31bd909f037f62bf67192c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2452302X |
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