MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription
Reactive oxygen species (ROS) promotes vascular injury and neointima formation in part by stimulating proliferation of vascular smooth muscle cells (VSMC). The underlying transcriptional mechanism, however, is not completely understood. Here we report that VSMC-specific deletion of MKL1 in mice supp...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231722003585 |
| _version_ | 1797954077208870912 |
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| author | Teng Wu Nan Li Qiumei Zhang Ruiqi Liu Hongwei Zhao Zhiwen Fan Lili Zhuo Yuyu Yang Yong Xu |
| author_facet | Teng Wu Nan Li Qiumei Zhang Ruiqi Liu Hongwei Zhao Zhiwen Fan Lili Zhuo Yuyu Yang Yong Xu |
| author_sort | Teng Wu |
| collection | DOAJ |
| description | Reactive oxygen species (ROS) promotes vascular injury and neointima formation in part by stimulating proliferation of vascular smooth muscle cells (VSMC). The underlying transcriptional mechanism, however, is not completely understood. Here we report that VSMC-specific deletion of MKL1 in mice suppressed neointima formation in a classic model of vascular injury. Likewise, pharmaceutical inhibition of MKL1 activity by CCG-1423 similarly mollified neointima formation in mice. Over-expression of a constitutively active MKL1 in vascular smooth muscle cells enhanced proliferation in a ROS-dependent manner. On the contrary, MKL1 depletion or inhibition attenuated VSMC proliferation. PCR array based screening identified forkhead box protein M1 (FOXM1) as a direct target for MKL1. MKL1 interacted with E2F1 to activate FOXM1 expression. Concordantly, FOXM1 depletion ameliorated MKL1-dependent VSMC proliferation. Of interest, ROS-induced MKL1 phosphorylation through MK2 was essential for its interaction with E2F1 and consequently FOXM1 trans-activation. Importantly, a positive correlation between FOXM1 expression and VSMC proliferation was identified in arterial specimens from patients with restenosis. Taken together, our data suggest that a redox-sensitive phosphorylation-switch of MKL1 activates FOXM1 transcription and mediates ROS fueled vascular smooth muscle proliferation. Targeting the MK-2/MKL1/FOXM1 axis may be considered as a reasonable approach for treatment of restenosis. |
| first_indexed | 2024-04-10T23:12:58Z |
| format | Article |
| id | doaj.art-0e571d6094a2431c8ea1f5c78fc8fbdd |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T23:12:58Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-0e571d6094a2431c8ea1f5c78fc8fbdd2023-01-13T04:16:20ZengElsevierRedox Biology2213-23172023-02-0159102586MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcriptionTeng Wu0Nan Li1Qiumei Zhang2Ruiqi Liu3Hongwei Zhao4Zhiwen Fan5Lili Zhuo6Yuyu Yang7Yong Xu8Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaDepartment of Human Anatomy, Nanjing Medical University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaKey Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaDepartment of Pathology, Nanjing Drum Tower Hospital Affiliated with Nanjing University School of Medicine, Nanjing, ChinaDepartment of Geriatrics, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China; Corresponding author. The Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjiayuan, Nanjing, 210000, China.Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China; Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China; Corresponding author. Nanjing Normal University, 1 Wenhuan Rd, Nanjing, 210046, China.Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China; Institute of Biomedical Research and College of Life Sciences, Liaocheng University, Liaocheng, China; Corresponding author. Nanjing Medical University, 101 Longmian Ave, Nanjing, 211166, China.Reactive oxygen species (ROS) promotes vascular injury and neointima formation in part by stimulating proliferation of vascular smooth muscle cells (VSMC). The underlying transcriptional mechanism, however, is not completely understood. Here we report that VSMC-specific deletion of MKL1 in mice suppressed neointima formation in a classic model of vascular injury. Likewise, pharmaceutical inhibition of MKL1 activity by CCG-1423 similarly mollified neointima formation in mice. Over-expression of a constitutively active MKL1 in vascular smooth muscle cells enhanced proliferation in a ROS-dependent manner. On the contrary, MKL1 depletion or inhibition attenuated VSMC proliferation. PCR array based screening identified forkhead box protein M1 (FOXM1) as a direct target for MKL1. MKL1 interacted with E2F1 to activate FOXM1 expression. Concordantly, FOXM1 depletion ameliorated MKL1-dependent VSMC proliferation. Of interest, ROS-induced MKL1 phosphorylation through MK2 was essential for its interaction with E2F1 and consequently FOXM1 trans-activation. Importantly, a positive correlation between FOXM1 expression and VSMC proliferation was identified in arterial specimens from patients with restenosis. Taken together, our data suggest that a redox-sensitive phosphorylation-switch of MKL1 activates FOXM1 transcription and mediates ROS fueled vascular smooth muscle proliferation. Targeting the MK-2/MKL1/FOXM1 axis may be considered as a reasonable approach for treatment of restenosis.http://www.sciencedirect.com/science/article/pii/S2213231722003585Transcriptional regulationPost-translational modificationVascular injuryVascular smooth muscle cellProliferationPhenotypic modulation |
| spellingShingle | Teng Wu Nan Li Qiumei Zhang Ruiqi Liu Hongwei Zhao Zhiwen Fan Lili Zhuo Yuyu Yang Yong Xu MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription Redox Biology Transcriptional regulation Post-translational modification Vascular injury Vascular smooth muscle cell Proliferation Phenotypic modulation |
| title | MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription |
| title_full | MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription |
| title_fullStr | MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription |
| title_full_unstemmed | MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription |
| title_short | MKL1 fuels ROS-induced proliferation of vascular smooth muscle cells by modulating FOXM1 transcription |
| title_sort | mkl1 fuels ros induced proliferation of vascular smooth muscle cells by modulating foxm1 transcription |
| topic | Transcriptional regulation Post-translational modification Vascular injury Vascular smooth muscle cell Proliferation Phenotypic modulation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231722003585 |
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