Mengxue Zhang1, Bowen Wang2, Go Urabe3, Yitao Huang4, Jorge Plutzky5, K Craig Kent2, Lian-Wang Guo6. 1. Department of Surgery, Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Cellular and Molecular Pathology Graduate Program, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA. 2. Department of Surgery, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. 3. Department of Surgery, Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Surgery, College of Medicine; Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. 4. Department of Surgery, Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. 5. Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. 6. Department of Surgery, Department of Physiology & Cell Biology, College of Medicine, Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA. Electronic address: lianwang.guo@osumc.edu.
Abstract
BACKGROUND: Vein-graft bypass is commonly performed to overcome atherosclerosis but is limited by high failure rates, principally due to neointimal wall thickening. Recent studies reveal that endothelial-mesenchymal transition (EndoMT) is critical for vein-graft neointima formation. BETs are a family of Bromo/ExtraTerminal domains-containing epigenetic reader proteins (BRD2, BRD3, BRD4). They bind acetylated histones through their unique tandem bromodomains (BD1, BD2), facilitating transcriptional complex formation and cell-state transitions. The role for BETs, including individual BRDs and their unique BDs, is not well understood in EndoMT and neointimal formation. METHODS AND RESULTS: Repression of BRD4 expression abrogated TGFβ1-induced EndoMT, with greater effects than BRD2 or BRD3 knockdown. An inhibitor selective for BD2 in all BETs, but not that for BD1, blocked EndoMT. Moreover, expression of a dominant-negative BRD4-specific BD2 fully abolished EndoMT. Concordantly, BRD4 knockdown repressed TGFβ1-stimulated increase of ZEB1 protein - a transcription factor integral in EndoMT. In vivo, lentiviral gene transfer of either BRD4 shRNA or dominant negative BRD4-specific BD2 mitigated neointimal development in rat jugular veins grafted to carotid arteries. CONCLUSIONS: Our data reveal the BD2 domain of BRD4 as a determinant driving EndoMT in vitro and neointimal formation in vivo. These findings provide new insight into BET biology, while offering prospects of specific BET domain targeting as an approach to limiting neointima and extending vein graft patency.
BACKGROUND: Vein-graft bypass is commonly performed to overcome atherosclerosis but is limited by high failure rates, principally due to neointimal wall thickening. Recent studies reveal that endothelial-mesenchymal transition (EndoMT) is critical for vein-graft neointima formation. BETs are a family of Bromo/ExtraTerminal domains-containing epigenetic reader proteins (BRD2, BRD3, BRD4). They bind acetylated histones through their unique tandem bromodomains (BD1, BD2), facilitating transcriptional complex formation and cell-state transitions. The role for BETs, including individual BRDs and their unique BDs, is not well understood in EndoMT and neointimal formation. METHODS AND RESULTS: Repression of BRD4 expression abrogated TGFβ1-induced EndoMT, with greater effects than BRD2 or BRD3 knockdown. An inhibitor selective for BD2 in all BETs, but not that for BD1, blocked EndoMT. Moreover, expression of a dominant-negative BRD4-specific BD2 fully abolished EndoMT. Concordantly, BRD4 knockdown repressed TGFβ1-stimulated increase of ZEB1 protein - a transcription factor integral in EndoMT. In vivo, lentiviral gene transfer of either BRD4 shRNA or dominant negative BRD4-specific BD2 mitigated neointimal development in rat jugular veins grafted to carotid arteries. CONCLUSIONS: Our data reveal the BD2 domain of BRD4 as a determinant driving EndoMT in vitro and neointimal formation in vivo. These findings provide new insight into BET biology, while offering prospects of specific BET domain targeting as an approach to limiting neointima and extending vein graft patency.
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