Endothelial OTUD1 promotes Ang II-induced vascular remodeling by deubiquitinating SMAD3
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ABSTRACT:
PROVIDER: PRJNA898372 | ENA |
REPOSITORIES: ENA
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Project description:Understanding the molecular mechanisms of pathological vascular remodeling is important for treating cardiovascular diseases and complications. Recent studies have highlighted a role of deubiquitinases in vascular pathophysiology. In this study, we investigated the role of a deubiquitinase, OTUD1, in angiotensin II (Ang II)-induced vascular remodeling. We identified upregulated OTUD1 in the vascular endothelium of Ang II-challenged mice and showed OTUD1 deletion attenuated vascular remodeling, collagen deposition, and EndMT. Conversely, OTUD1 overexpression aggravated these pathological changes both in vivo and in vitro. Mechanistically, SMAD3 was identified as a substrate of OTUD1 using co-immunoprecipitation followed with LC-MS/MS. We found OTUD1 stabilizes SMAD3 and facilitates SMAD3/SMAD4 complex formation and subsequent nuclear translocation through both K48- and K63-linked deubiquitination. OTUD1-mediated SMAD3 activation regulate the transcription of genes involved in vascular EndMT and remodeling in HUVECs. Finally, SMAD3 inhibition reversed OTUD1-promoted vascular remodeling. Our findings demonstrate endothelial OTUD1 promoted Ang II-induced vascular remodeling by deubiquitinating SMAD3. This study identified SMAD3 as a target of OTUD1 and indicates OTUD1 as a potential therapeutic target for the diseases related to vascular remodeling.
2022-12-24 | GSE217304 | GEO
Project description:Understanding the molecular mechanisms of pathological vascular remodeling is important for treating cardiovascular diseases and complications. Recent studies have highlighted a role of deubiquitinases in vascular pathophysiology. In this study, we investigated the role of a deubiquitinase, OTUD1, in angiotensin II (Ang II)-induced vascular remodeling. We identified upregulated OTUD1 in the vascular endothelium of Ang II-challenged mice and showed OTUD1 deletion attenuated vascular remodeling, collagen deposition, and EndMT. Conversely, OTUD1 overexpression aggravated these pathological changes both in vivo and in vitro. Mechanistically, SMAD3 was identified as a substrate of OTUD1 using co-immunoprecipitation followed with LC-MS/MS. We found OTUD1 stabilizes SMAD3 and facilitates SMAD3/SMAD4 complex formation and subsequent nuclear translocation through both K48- and K63-linked deubiquitination. OTUD1-mediated SMAD3 activation regulate the transcription of genes involved in vascular EndMT and remodeling in HUVECs. Finally, SMAD3 inhibition reversed OTUD1-promoted vascular remodeling. Our findings demonstrate endothelial OTUD1 promoted Ang II-induced vascular remodeling by deubiquitinating SMAD3. This study identified SMAD3 as a target of OTUD1 and indicates OTUD1 as a potential therapeutic target for the diseases related to vascular remodeling.
2022-12-24 | PXD037926 | Pride
Project description:Increased level of angiotensin II (Ang II) plays a central role in the development of hypertensive vascular remodeling. Here, we identify the deubiquitinating enzyme JOSD2 as a protective factor and investigate its molecular mechanism in Ang II-induced vascular remodeling. Firstly, we found that JOSD2 was up-regulated in aortic smooth muscle cells but not endothelial cells of Ang II-challenged mouse vascular tissues. Whole-body knockout of JOSD2 significantly deteriorated Ang II-induced vascular remodeling in mice. Conversely, Ang II-induced vascular remodeling was reversed by VSMC-specific JOSD2 overexpression. In vitro, JOSD2 deficiency aggravated the fibrosis, proliferation, and migration induced by Ang II in vascular smooth muscle cells (VSMCs), while these changes were reversed by JOSD2 overexpression. RNA-seq analysis showed that the protective effects of JOSD2 in VSMCs were related to TGFβ-SMAD pathway. Furthermore, the LC-MS/MS analysis identified SMAD7, a negative regulator in TGFβ-SMAD pathway, as the substrate of JOSD2. JOSD2 specifically bound to the MH1 domain of SMAD7 to removed K48-linked Ub chains of SMAD7 at lysine 220 to sustain SMAD7 stability. Taken together, our finding reveals that JOSD2-SMAD7 axis is critical for relieving Ang II-induced vascular remodeling and JOSD2 maybe a novel and potential therapeutic target for hypertensive vascular remodeling.
2024-10-18 | GSE279358 | GEO
Project description:Increased level of angiotensin II (Ang II) plays a central role in the development of hypertensive vascular remodeling. Here, we identify the deubiquitinating enzyme JOSD2 as a protective factor and investigate its molecular mechanism in Ang II-induced vascular remodeling. Firstly, we found that JOSD2 was up-regulated in aortic smooth muscle cells but not endothelial cells of Ang II-challenged mouse vascular tissues. Whole-body knockout of JOSD2 significantly deteriorated Ang II-induced vascular remodeling in mice. Conversely, Ang II-induced vascular remodeling was reversed by VSMC-specific JOSD2 overexpression. In vitro, JOSD2 deficiency aggravated the fibrosis, proliferation, and migration induced by Ang II in vascular smooth muscle cells (VSMCs), while these changes were reversed by JOSD2 overexpression. RNA-seq analysis showed that the protective effects of JOSD2 in VSMCs were related to TGFβ-SMAD pathway. Furthermore, the LC-MS/MS analysis identified SMAD7, a negative regulator in TGFβ-SMAD pathway, as the substrate of JOSD2. JOSD2 specifically bound to the MH1 domain of SMAD7 to removed K48-linked Ub chains of SMAD7 at lysine 220 to sustain SMAD7 stability. Taken together, our finding reveals that JOSD2-SMAD7 axis is critical for relieving Ang II-induced vascular remodeling and JOSD2 maybe a novel and potential therapeutic target for hypertensive vascular remodeling.
2024-10-10 | PXD056674 | Pride
Project description:Deubiquitinating enzymes have gained more and more attention in the field of pathological cardiac hypertrophy. In this study, we explored the role of a deubiquitinase, OTUD1, in the transverse aortic constriction (TAC) induced cardiac hypertrophy. We found the upregulation of OTUD1 in heart tissues of TAC mice. OTUD1 overexpression promoted cardiac hypertrophy, cardiac fibrosis and apoptosis. Conversely, OTUD1 depletion alleviated these pathological changes both in vivo and in vitro. Mechanistically, ASK1 was identified as one substrate of OTUD1 using co-immunoprecipitation followed with LC-MS/MS. Interestingly, OTUD1 didn’t deubiquitinate ASK1, but increased the phosphorylation level of ASK1 during the process of cardiac hypertrophy. We found that PGAM5, the upper stream regulator of ASK1, was stabilized by OTUD1 in a K63 ubiquitin chain dependent way, which reminded us OTUD1 increased the phosphorylation level of ASK1 by deubiquitinating PGAM5. This study identified the OTUD1-ASK1 axis as a potential therapeutic target for pathological cardiac hypertrophy.
2023-09-05 | GSE241809 | GEO
Project description:Understanding the molecular mechanisms of pathological vascular remodeling is important for treating cardiovascular diseases and complications. Recent studies have highlighted a role of deubiquitinases in vascular pathophysiology. Here, we investigate the role of a deubiquitinase, OTUD1, in angiotensin II (Ang II)-induced vascular remodeling. We detect upregulated OTUD1 in the vascular endothelium of Ang II-challenged mice and show that OTUD1 deletion attenuates vascular remodeling, collagen deposition, and EndMT. Conversely, OTUD1 overexpression aggravates these pathological changes both in vivo and in vitro. Mechanistically, SMAD3 is identified as a substrate of OTUD1 using co-immunoprecipitation followed by LC-MS/MS. We find that OTUD1 stabilizes SMAD3 and facilitates SMAD3/SMAD4 complex formation and subsequent nuclear translocation through both K48- and K63-linked deubiquitination. OTUD1-mediated SMAD3 activation regulates transcription of genes involved in vascular EndMT and remodeling in HUVECs. Finally, SMAD3 inhibition reverses OTUD1-promoted vascular remodeling. Our findings demonstrate that endothelial OTUD1 promotes Ang II-induced vascular remodeling by deubiquitinating SMAD3. We identify SMAD3 as a target of OTUD1 and propose OTUD1 as a potential therapeutic target for diseases related to vascular remodeling.
| S-EPMC9986815 | biostudies-literature
Project description:Understanding the molecular mechanisms of pathological vascular remodeling is important for treating cardiovascular diseases and complications. Recent studies have highlighted a role of deubiquitinases in vascular pathophysiology. Here, we investigate the role of a deubiquitinase, OTUD1, in angiotensin II (Ang II)-induced vascular remodeling. We detect upregulated OTUD1 in the vascular endothelium of Ang II-challenged mice and show that OTUD1 deletion attenuates vascular remodeling, collagen deposition, and EndMT. Conversely, OTUD1 overexpression aggravates these pathological changes both in vivo and in vitro. Mechanistically, SMAD3 is identified as a substrate of OTUD1 using co-immunoprecipitation followed by LC-MS/MS. We find that OTUD1 stabilizes SMAD3 and facilitates SMAD3/SMAD4 complex formation and subsequent nuclear translocation through both K48- and K63-linked deubiquitination. OTUD1-mediated SMAD3 activation regulates transcription of genes involved in vascular EndMT and remodeling in HUVECs. Finally, SMAD3 inhibition reverses OTUD1-promoted vascular remodeling. Our findings demonstrate that endothelial OTUD1 promotes Ang II-induced vascular remodeling by deubiquitinating SMAD3. We identify SMAD3 as a target of OTUD1 and propose OTUD1 as a potential therapeutic target for diseases related to vascular remodeling.
| S-SCDT-10_15252-EMBR_202256135 | biostudies-other
Project description:Atherosclerosis is a persistent inflammatory state accompanied by lipid overload. Vascular fibrosis is one of the primary causes of atherosclerosis development. Although ligustilide (Lig) was shown to exert obvious antiatherogenic effects in previous studies, its precise mechanism has not been comprehensively discussed. In this paper, pharmacologic studies were performed to explore the pharmacodynamic effects of Lig on protecting aorta vascular wall structures and modulating serum inflammatory factors in ApoE-/- mice. Chemical proteomics based on a Lig-derived photoaffinity labelling (Lig-PAL) probe were applied to identify potential therapeutic targets. Mothers against decapentaplegic homologue 3 (SMAD3), which is closely related to the development of vascular fibrosis and atherosclerosis, was identified as a potential target of Lig. Lig suppressed the phosphorylation and nuclear translocation of SMAD3 by blocking the interaction between SMAD3 and transforming growth factor-β (TGF-β) receptor 1, thereby inhibiting the collagen synthesis process, preventing vascular fibrosis and improving atherosclerosis. The quantitative proteomics results from Lig-treated atherosclerotic ApoE-/- mice also indicated that Lig inhibits the expression of collagens I and III, interferes with collagen fibril organization processes and protects the aorta from vascular fibrosis. Hence, developing a novel SMAD3 inhibitor may present another therapeutic option for preventing atherosclerosis.
2020-01-21 | PXD017125 | Pride
Project description:Angiotensin II (Ang II)-mediated vascular smooth muscle cells (VSMC) dysfunction plays a critical role in cardiovascular diseases. However, the gene expression in this process is unclear. We used Rat Affymetrix gene array to profile Ang II-regulated gene in RVSMC and evaluated their role in VSMC dysfunction. Examined 4 samples of Rat VSMC in triplicate. Control (without Ang II treatment) and 3 samples treated with Ang II for 6h, 12h, and 24h. Compared the changes in gene expression in Ang II treated samples relative to control samples.
2012-03-23 | E-GEOD-35627 | biostudies-arrayexpress
Project description:Angiotensin II (Ang II)-mediated vascular smooth muscle cells (VSMC) dysfunction plays a critical role in cardiovascular diseases. However, the gene expression in this process is unclear. We used Rat Affymetrix gene array to profile Ang II-regulated gene in RVSMC and evaluated their role in VSMC dysfunction.
2012-03-23 | GSE35627 | GEO