Su Wang, Hengjuan Liu, Junxia Hu, Ting Li, Bowen Li
{"title":"Cdc42/Rac1通路:缺铁性主动脉内侧变性背后的分子机制。","authors":"Su Wang, Hengjuan Liu, Junxia Hu, Ting Li, Bowen Li","doi":"10.62347/YISX1726","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>To elucidate the underlying mechanism of iron deficiency augmented Angiotensin II-induced aortic medial degeneration.</p><p><strong>Methods: </strong>ApoE<sup>-/-</sup> mice were randomly divided into four groups: normal control group (NC group), Angiotensin II (Ang II) subcutaneous pumped alone Group (Ang II group), iron deficiency (ID) group (ID group) and ID+Ang II group. The survival time, systolic blood pressure (SBP), and aortic medial degeneration (AMD) formation were monitored. Iron deposition in the aortas was assessed using Prussian blue iron staining. The expression of iron metabolism indicators, aortopathies and the cytoskeleton of vascular smooth muscle cells (VSMCs) were analyzed. In an in vitro setting, deferoxamine (DFO) was employed to mimic ID to examine the effects of Ang II on the cytoskeletal and contractile function of VSMCs during ID. Ras-related C3 botulinum toxin substrate 1 (Rac-1) expression was inhibited with EHT1864 to verify the role of Cdc42/Rac1 pathway in this pathological process. Blood samples were collected from 150 patients with aortic dissection (AD) and 60 patients with hypertension who were admitted to the Department of Cardiovascular Surgery at Renmin Hospital of Wuhan University between June 2018 and September 2019. The aortic tissues were obtained during the surgical treatment of Stanford type A AD patients and the heart donor. The iron metabolism status in plasma and aortic tissue was analyzed.</p><p><strong>Results: </strong>In vivo experiments revealed that, in comparison to the NC and ID groups, mice in the Ang II and ID+Ang II groups exhibited increased SBP, significantly reduced survival time, and an expanded range of aortic dissection (P < 0.05). ID feeding augmented the Ang II-induced aortopathies. Both in vitro and in vivo results indicated that ID led to diminished expression of phosphorylated myosin light chain (p-MLC) and recombinant Cell Division Cycle Protein 42 (Cdc42) in VSMCs, while Rac-1 expression increased. The clinical sample testing data further confirmed the discovery that individuals diagnosed with AD display ID in both the plasma and the diseased aortas.</p><p><strong>Conclusions: </strong>The Cdc42/Rac1 pathway plays a crucial role in disrupting the cytoskeleton of vascular smooth muscle cells during iron deficiency, which leads to aortic medial degeneration both in vivo and in vitro.</p>","PeriodicalId":7731,"journal":{"name":"American journal of translational research","volume":null,"pages":null},"PeriodicalIF":1.7000,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11384388/pdf/","citationCount":"0","resultStr":"{\"title\":\"The Cdc42/Rac1 pathway: a molecular mechanism behind iron-deficiency-driven aortic medial degeneration.\",\"authors\":\"Su Wang, Hengjuan Liu, Junxia Hu, Ting Li, Bowen Li\",\"doi\":\"10.62347/YISX1726\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>To elucidate the underlying mechanism of iron deficiency augmented Angiotensin II-induced aortic medial degeneration.</p><p><strong>Methods: </strong>ApoE<sup>-/-</sup> mice were randomly divided into four groups: normal control group (NC group), Angiotensin II (Ang II) subcutaneous pumped alone Group (Ang II group), iron deficiency (ID) group (ID group) and ID+Ang II group. The survival time, systolic blood pressure (SBP), and aortic medial degeneration (AMD) formation were monitored. Iron deposition in the aortas was assessed using Prussian blue iron staining. The expression of iron metabolism indicators, aortopathies and the cytoskeleton of vascular smooth muscle cells (VSMCs) were analyzed. In an in vitro setting, deferoxamine (DFO) was employed to mimic ID to examine the effects of Ang II on the cytoskeletal and contractile function of VSMCs during ID. Ras-related C3 botulinum toxin substrate 1 (Rac-1) expression was inhibited with EHT1864 to verify the role of Cdc42/Rac1 pathway in this pathological process. Blood samples were collected from 150 patients with aortic dissection (AD) and 60 patients with hypertension who were admitted to the Department of Cardiovascular Surgery at Renmin Hospital of Wuhan University between June 2018 and September 2019. The aortic tissues were obtained during the surgical treatment of Stanford type A AD patients and the heart donor. The iron metabolism status in plasma and aortic tissue was analyzed.</p><p><strong>Results: </strong>In vivo experiments revealed that, in comparison to the NC and ID groups, mice in the Ang II and ID+Ang II groups exhibited increased SBP, significantly reduced survival time, and an expanded range of aortic dissection (P < 0.05). ID feeding augmented the Ang II-induced aortopathies. Both in vitro and in vivo results indicated that ID led to diminished expression of phosphorylated myosin light chain (p-MLC) and recombinant Cell Division Cycle Protein 42 (Cdc42) in VSMCs, while Rac-1 expression increased. The clinical sample testing data further confirmed the discovery that individuals diagnosed with AD display ID in both the plasma and the diseased aortas.</p><p><strong>Conclusions: </strong>The Cdc42/Rac1 pathway plays a crucial role in disrupting the cytoskeleton of vascular smooth muscle cells during iron deficiency, which leads to aortic medial degeneration both in vivo and in vitro.</p>\",\"PeriodicalId\":7731,\"journal\":{\"name\":\"American journal of translational research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.7000,\"publicationDate\":\"2024-08-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11384388/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of translational research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.62347/YISX1726\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q3\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of translational research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.62347/YISX1726","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
目的方法:将载脂蛋白E-/-小鼠随机分为四组:正常对照组(NC组)、单独使用血管紧张素II(Ang II)皮下注射组(Ang II组)、缺铁诱导主动脉内膜变性的潜在机制:方法:将载脂蛋白E-/-小鼠随机分为四组:正常对照组(NC组)、单独皮下注射血管紧张素II组(Ang II组)、缺铁组(ID组)和ID+Ang II组。研究人员对患者的存活时间、收缩压(SBP)和主动脉内侧变性(AMD)的形成进行了监测。使用普鲁士蓝铁染色法评估主动脉中的铁沉积。分析了铁代谢指标的表达、主动脉病变和血管平滑肌细胞(VSMC)的细胞骨架。在体外环境中,采用去氧胺(DFO)模拟ID,研究ID期间Ang II对血管平滑肌细胞的细胞骨架和收缩功能的影响。用EHT1864抑制Ras相关的C3肉毒毒素底物1(Rac-1)的表达,以验证Cdc42/Rac1通路在这一病理过程中的作用。研究人员采集了2018年6月至2019年9月期间武汉大学人民医院心血管外科收治的150名主动脉夹层(AD)患者和60名高血压患者的血样。主动脉组织是在斯坦福A型AD患者和心脏供体的手术治疗过程中获得的。分析了血浆和主动脉组织中的铁代谢状况:体内实验显示,与NC组和ID组相比,Ang II组和ID+Ang II组小鼠SBP升高,存活时间显著缩短,主动脉夹层范围扩大(P < 0.05)。饲喂 ID 会加重 Ang II 诱导的主动脉病变。体外和体内研究结果表明,ID导致VSMC中磷酸化肌球蛋白轻链(p-MLC)和重组细胞分裂周期蛋白42(Cdc42)的表达减少,而Rac-1的表达增加。临床样本检测数据进一步证实了这一发现,即确诊为AD的患者在血浆和病变主动脉中都显示出ID:结论:缺铁时,Cdc42/Rac1通路在破坏血管平滑肌细胞的细胞骨架中起着关键作用,从而导致体内和体外主动脉内侧变性。
The Cdc42/Rac1 pathway: a molecular mechanism behind iron-deficiency-driven aortic medial degeneration.
Objective: To elucidate the underlying mechanism of iron deficiency augmented Angiotensin II-induced aortic medial degeneration.
Methods: ApoE-/- mice were randomly divided into four groups: normal control group (NC group), Angiotensin II (Ang II) subcutaneous pumped alone Group (Ang II group), iron deficiency (ID) group (ID group) and ID+Ang II group. The survival time, systolic blood pressure (SBP), and aortic medial degeneration (AMD) formation were monitored. Iron deposition in the aortas was assessed using Prussian blue iron staining. The expression of iron metabolism indicators, aortopathies and the cytoskeleton of vascular smooth muscle cells (VSMCs) were analyzed. In an in vitro setting, deferoxamine (DFO) was employed to mimic ID to examine the effects of Ang II on the cytoskeletal and contractile function of VSMCs during ID. Ras-related C3 botulinum toxin substrate 1 (Rac-1) expression was inhibited with EHT1864 to verify the role of Cdc42/Rac1 pathway in this pathological process. Blood samples were collected from 150 patients with aortic dissection (AD) and 60 patients with hypertension who were admitted to the Department of Cardiovascular Surgery at Renmin Hospital of Wuhan University between June 2018 and September 2019. The aortic tissues were obtained during the surgical treatment of Stanford type A AD patients and the heart donor. The iron metabolism status in plasma and aortic tissue was analyzed.
Results: In vivo experiments revealed that, in comparison to the NC and ID groups, mice in the Ang II and ID+Ang II groups exhibited increased SBP, significantly reduced survival time, and an expanded range of aortic dissection (P < 0.05). ID feeding augmented the Ang II-induced aortopathies. Both in vitro and in vivo results indicated that ID led to diminished expression of phosphorylated myosin light chain (p-MLC) and recombinant Cell Division Cycle Protein 42 (Cdc42) in VSMCs, while Rac-1 expression increased. The clinical sample testing data further confirmed the discovery that individuals diagnosed with AD display ID in both the plasma and the diseased aortas.
Conclusions: The Cdc42/Rac1 pathway plays a crucial role in disrupting the cytoskeleton of vascular smooth muscle cells during iron deficiency, which leads to aortic medial degeneration both in vivo and in vitro.