Small GTP-Binding Protein GDP Dissociation Stimulator Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells

Nogi, Masamichi; Satoh, Kimio; Sunamura, Shinichiro; Kikuchi, Nobuhiro; Satoh, Taijyu; Kurosawa, Ryo; Omura, Junichi; Elias-Al-Mamun, Md.; Siddique, Mohammad Abdul Hai; Numano, Kazuhiko; Kudo, S.; Miyata, Satoshi; Akiyama, Mitoshi; Kumagai, Koji; Kawamoto, Shunsuke; Saiki, Yoshikatsu; Shimokawa, Hiroaki

doi:10.1161/circulationaha.118.035648

Cited by 42 publications

(39 citation statements)

References 63 publications

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“…Nogi M et al reported that disruption and degradation of medial elastic lamina in the ascending aorta were more severe in ApoE −/-SmgGDS ± mice compared with ApoE −/mice after AngII infusion for 4 weeks. However, there was no significant difference in the disruption and degradation of the medial elastic lamina in the abdominal aorta between the two genotypes after AngII infusion [29]. Therefore, it was no surprising to find that TRPV1 expression was decreased in AngII-induced abdominal aortic aneurysm mouse models.…”

Section: Discussionmentioning

confidence: 96%

TRPV1 inhibits smooth muscle cell phenotype switching in a mouse model of abdominal aortic aneurysm

Wang

Jia

2020

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The natural outcome of abdominal aortic aneurysm (AAA) is that of slow progression and ultimate rupture, then a life-threatening hemorrhage consequently. Ruptured AAA is a dramatic catastrophe and constitutes one of the leading causes of acute death in elderly men. However, the mechanism of AAA is still unclear. Transient receptor potential vanilloid (TRPV) family has protective effects in cardiovascular diseases. In this study, we revealed the expression and the pathogenesis of TRPV1 in a mouse AAA model. The results presented here identify TRPV1 could be a potential therapeutic target for AAA treatment. ARTICLE HISTORY

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Section: Discussionmentioning

confidence: 96%

TRPV1 inhibits smooth muscle cell phenotype switching in a mouse model of abdominal aortic aneurysm

Wang

Jia

2020

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“…In the present study, Ang II induced loss of the contractile phenotype and gain of the synthetic phenotype as evidenced by decreased ACTA2 and MYH11 expression and increased SPP1 and vimentin expression in mAoSMCs, suggesting a phenotypic switch. Induction of AoSMC switching from a normal contractile to a synthetic phenotype with mutations of ACTA2 and MYH11 promotes secretion of MMPs, inflammatory cytokines and growth factors, resulting in ECM degradation and aortic wall weakening and thus TAD rupture (Liu et al., 2017; Nogi et al., 2018). Destruction of the elastin‐contractile unit causes impaired function of AoSMCs, leading to aortic wall dilatation and failure (Nogi et al., 2018).…”

Section: Discussionmentioning

confidence: 99%

Insulin‐like growth factor‐binding protein 3 inhibits angiotensin II‐induced aortic smooth muscle cell phenotypic switch and matrix metalloproteinase expression

Chen

Zhong

et al. 2020

Experimental Physiology

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New Findings What is the central question of this study?Insulin‐like growth factor 1 and its major binding protein insulin‐like growth factor binding protein 3 (IGFBP3) are involved in collagen deregulation in several cardiovascular diseases: what is the role of IGFBP3 in thoracic aortic dissection and does it regulate aortic smooth muscle cells’ phenotypic switch? What is the main finding and its importance?IGFBP3 inhibits aortic smooth muscle cells’ phenotypic switch from a contractile to a synthetic phenotype, decreases matrix metalloproteinase 9 activation and suppresses elastin degradation. These findings provide a better understanding of the pathogenesis of thoracic aortic dissection. Abstract Thoracic aortic dissection (TAD) is characterized by aortic media degeneration and is a highly lethal disease. An aortic smooth muscle cell (AoSMC) phenotypic switch is considered a key pathophysiological change in TAD. Insulin‐like growth factor binding protein 3 (IGFBP3) was found to be downregulated in aortic tissues of TAD patients. The present work aimed to study the function of IGFBP3 in AoSMCs’ phenotypic switch and matrix metalloproteinase (MMP) expression. We established a mouse model of TAD by angiotensin (Ang) II infusion to β‐aminopropionitrile‐administrated mice, and found decreased IGFBP3 expression accompanied by aortic dilatation and elastin degradation in vivo. Further, mouse (m)AoSMCs were isolated from mouse thoracic aorta and treated with Ang II. Ang II induced downregulation of IGFBP3 in vitro. To further study the function of IGFBP3, primary mAoSMCs were infected with adenovirus expressing IGFBP3 followed by Ang II induction. Enforced upregulation of IGFBP3 decreased MMP9 expression and activation as well as increasing tissue inhibitor of metalloproteinase (TIMP) 1 expression in Ang II‐induced mAoSMCs. No difference was observed in MMP2 and TIMP3 expression. IGFBP3 suppressed subsequent Ang II‐induced elastin degradation in vitro. IGFBP3 inhibited Ang II‐induced mAoSMCs’ phenotypic switch as evidenced by increased smooth muscle actin α‐2 (ACTA2) and myosin heavy chain 11 (MYH11) expression and decreased secreted phosphoprotein 1 (SPP1) and vimentin expression. Taken together, the present study demonstrates the role of IGFBP3 in preserving AoSMCs’ contractile state and reducing MMP9 activation and thus promoting elastic fibre synthesis, which provides a better understanding of the pathogenesis of TAD.

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“…Finally, we evaluated the levels of cytosolic ROS after treatment with the 25 analogs and found that the analog b significantly reduced ROS in PAH-PASMCs ( Figure 2G). Because we previously confirmed that intracellular ROS in PAH-PASMCs is increased compared with control PASMCs 19 and higher levels of cytosolic ROS are mechanistically involved in the proliferation of PAH-PASMCs, 19,27,28 we used the analog b in the following experiments in vivo and in vitro.…”

Section: Development Of Celastramycin Analogues and Their Structure-amentioning

confidence: 99%

Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension

Kurosawa

Satoh²,

Kikuchi³

et al. 2019

Circulation Research

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Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH. Objective: We aimed to discover a novel drug for PAH that inhibits PASMC proliferation. Methods and Results: We screened 5562 compounds from original library using high-throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole-type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1α (hypoxia-inducible factor 1α), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domaincontaining protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs. Conclusions: These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.

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Small GTP-Binding Protein GDP Dissociation Stimulator Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells

Cited by 42 publications

References 63 publications

TRPV1 inhibits smooth muscle cell phenotype switching in a mouse model of abdominal aortic aneurysm

TRPV1 inhibits smooth muscle cell phenotype switching in a mouse model of abdominal aortic aneurysm

Insulin‐like growth factor‐binding protein 3 inhibits angiotensin II‐induced aortic smooth muscle cell phenotypic switch and matrix metalloproteinase expression

Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension

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