Author + information
- Received July 5, 2018
- Revision received July 31, 2018
- Accepted August 23, 2018
- Published online December 31, 2018.
- Mengxue Zhang, MD, MSa,b,∗,
- Go Urabe, MD, PhDa,c,∗,
- Christopher Little, MDd,∗,
- Bowen Wang, PhDc,
- Alycia M. Kentd,
- Yitao Huang, BSa,
- K. Craig Kent, MDc,∗∗ ( and )
- Lian-Wang Guo, PhDa,∗ ()
- aDepartment of Surgery and Department of Physiology and Cell Biology, College of Medicine, and the Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio
- bCellular and Molecular Pathology Graduate Program, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
- cDepartment of Surgery, College of Medicine, and the Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio
- dDepartment of Surgery, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin
- ↵∗Address for correspondence:
Dr. Lian-Wang Guo, Department of Surgery and Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio 43210.
- ↵∗∗Dr. K. Craig Kent, Department of Surgery, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, Ohio 43210.
• 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.
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.
↵∗ Drs. Zhang, Urabe, and Little contributed equally to this work and are joint first authors.
This work was supported by National Institutes of Health grants R01HL133665 (to Dr. Guo), R01HL-068673 (to Dr. Kent), and R01HL143469 (to Drs. Kent and Guo), and an American Heart Association pre-doctoral award (17PRE33670865 to Dr. Zhang). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received July 5, 2018.
- Revision received July 31, 2018.
- Accepted August 23, 2018.
- 2018 The Authors