Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

Li, Na; Yi, Xin; He, Yi; Huo, Bo; Chen, Yue; Zhang, Zihao; Li, Yang; Zhong, Xiaoxuan; Li, Rui; Zhu, Xiashi; Fang, Zemin; Wei, Xiang; Jiang, Ding‐Sheng

doi:10.7150/ijbs.72528

Cited by 65 publications

(50 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A lactate dehydrogenase (LDH) assay was performed to evaluate the toxicity of JIB-04 on HASMCs by a Cytotoxicity LDH Assay Kit-WST (CK12, Dojindo) as reported previously [ 41 ]. A total of 8 × 10 3 cells/100 μL per well were plated in 96-well plates, which were treated with a JIB-04 concentration gradient (0, 0.1, 0.25, 0.5, 1 μmol/L) for 24 h. Then, 10 μL of lysis buffer was added to the high contrast well and incubated at 37 °C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

JIB-04, a histone demethylase Jumonji C domain inhibitor, regulates phenotypic switching of vascular smooth muscle cells

Zhang

et al. 2022

Clin Epigenet

Self Cite

View full text Add to dashboard Cite

Background Vascular smooth muscle cell (VSMC) phenotype switching is critical for neointima formation, which is the major cause of restenosis after stenting or coronary artery bypass grafting. However, the epigenetic mechanisms regulating phenotype switching of VSMCs, especially histone methylation, are not well understood. As a main component of histone lysine demethylases, Jumonji demethylases might be involved in VSMC phenotype switching and neointima formation. Methods and results A mouse carotid injury model and VSMC proliferation model were constructed to investigate the relationship between histone methylation of H3K36 (downstream target molecule of Jumonji demethylase) and neointima formation. We found that the methylation levels of H3K36 negatively correlated with VSMC proliferation and neointima formation. Next, we revealed that JIB-04 (a pan-inhibitor of the Jumonji demethylase superfamily) could increase the methylation levels of H3K36. Furthermore, we found that JIB-04 obviously inhibited HASMC proliferation, and a cell cycle assay showed that JIB-04 caused G2/M phase arrest in HASMCs by inhibiting the phosphorylation of RB and CDC2 and promoting the phosphorylation of CHK1. Moreover, JIB-04 inhibited the expression of MMP2 to suppress the migration of HASMCs and repressed the expression of contraction-related genes. RNA sequencing analysis showed that the biological processes associated with the cell cycle and autophagy were enriched by using Gene Ontology analysis after HASMCs were treated with JIB-04. Furthermore, we demonstrated that JIB-04 impairs autophagic flux by downregulating STX17 and RAB7 expression to inhibit the fusion of autophagosomes and lysosomes. Conclusion JIB-04 suppresses the proliferation, migration, and contractile phenotype of HASMCs by inhibiting autophagic flux, which indicates that JIB-04 is a promising reagent for the treatment of neointima formation.

show abstract

Section: Methodsmentioning

confidence: 99%

JIB-04, a histone demethylase Jumonji C domain inhibitor, regulates phenotypic switching of vascular smooth muscle cells

Zhang

et al. 2022

Clin Epigenet

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ferroptosis is critical in the occurrence and development of AAD. In Stanford type A aortic dissection patients, the levels of TfR and HMOX1 were upregulated and SLC7A11 and GPX4 were downregulated [ 46 ]. In addition, upregulated expression of HMOX1, TfR and 4-hydroxynonenal (4-HNE) was detected in β-Aminopropionitrile (BAPN)-induced AAD mice ( Table 1 ) [ 46 ].…”

Section: Iron Metabolism Ferroptosis and Cardiovascular Diseasesmentioning

confidence: 99%

“…In Stanford type A aortic dissection patients, the levels of TfR and HMOX1 were upregulated and SLC7A11 and GPX4 were downregulated [ 46 ]. In addition, upregulated expression of HMOX1, TfR and 4-hydroxynonenal (4-HNE) was detected in β-Aminopropionitrile (BAPN)-induced AAD mice ( Table 1 ) [ 46 ]. Administration of liproxstatin-1 (Lip-1) improved AAD incidence and death rates and alleviated medial degeneration through the suppression of ferroptosis ( Table 1 ) [ 46 ].…”

Section: Iron Metabolism Ferroptosis and Cardiovascular Diseasesmentioning

confidence: 99%

“…In addition, upregulated expression of HMOX1, TfR and 4-hydroxynonenal (4-HNE) was detected in β-Aminopropionitrile (BAPN)-induced AAD mice ( Table 1 ) [ 46 ]. Administration of liproxstatin-1 (Lip-1) improved AAD incidence and death rates and alleviated medial degeneration through the suppression of ferroptosis ( Table 1 ) [ 46 ]. Moreover, treatment with BRD4770 inhibited aortic dilation and reduced morbidity and mortality in BAPN-induced aortic dissection through the prevention of ferroptosis, lipid peroxidation and inflammation [ 63 ].…”

Section: Iron Metabolism Ferroptosis and Cardiovascular Diseasesmentioning

confidence: 99%

“…Additionally, Lip-1 improved cardiac dysfunction in myocardial I/R injury mice by reducing iron accumulation and mitigating ROS generation ( Table 3 ) [ 77 ]. In BAPN-induced AAD mice, administration of Lip-1 downregulated the incidence and mortality of AAD and improved medial degeneration by blocking iron accumulation and excessive oxidative stress ( Table 1 and Table 3 ) [ 46 ].…”

Section: Targeting Iron Metabolism and Ferroptosis In Cardiovascular ...mentioning

confidence: 99%

See 2 more Smart Citations

Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases

Chen

Wang

et al. 2023

Nutrients

View full text Add to dashboard Cite

Iron functions as an essential micronutrient and participates in normal physiological and biochemical processes in the cardiovascular system. Ferroptosis is a novel type of iron-dependent cell death driven by iron accumulation and lipid peroxidation, characterized by depletion of glutathione and suppression of glutathione peroxidase 4 (GPX4). Dysregulation of iron metabolism and ferroptosis have been implicated in the occurrence and development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, pulmonary hypertension, myocardial ischemia/reperfusion injury, cardiomyopathy, and heart failure. Iron chelators deferoxamine and dexrazoxane, and lipophilic antioxidants ferrostatin-1 and liproxstatin-1 have been revealed to abolish ferroptosis and suppress lipid peroxidation in atherosclerosis, cardiomyopathy, hypertension, and other CVDs. Notably, inhibition of ferroptosis by ferrostatin-1 has been demonstrated to alleviate cardiac impairments, fibrosis and pathological remodeling during hypertension by potentiating GPX4 signaling. Administration of deferoxamine improved myocardial ischemia/reperfusion injury by inhibiting lipid peroxidation. Several novel small molecules may be effective in the treatment of ferroptosis-mediated CVDs. In this article, we summarize the regulatory roles and underlying mechanisms of iron metabolism dysregulation and ferroptosis in the occurrence and development of CVDs. Targeting iron metabolism and ferroptosis are potential therapeutic strategies in the prevention and treatment of hypertension and other CVDs.

show abstract

Decoding the biology and clinical implication of neutrophils in intracranial aneurysm

Ji,

Han,

Danyang Jie

et al. 2024

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveAbundant neutrophils have been identified in both ruptured and unruptured intracranial aneurysm (IA) domes, with their function and clinical implication being poorly characterized.Materials and MethodsWe employed single‐cell RNA sequencing (scRNA‐Seq) datasets of both human and murine model, and external bulk mRNA sequencing datasets to thoroughly explore the features and functional heterogeneous of neutrophils infiltrating the IA dome.ResultsWe found that both unruptured and ruptured IA dome contain a substantial population of neutrophils, characterized by FCGR3B, G0S2, CSF3R, and CXCR2. These cells exhibited heterogeneity in terms of function and differentiation. Despite similar transcriptional activation, neutrophils in IA dome expressed a repertoire of gene programs that mimicked transcriptomic alterations observed from bone marrow to peripheral blood, showing self‐similarity. In addition, the recruitment of neutrophils in unruptured IA was primarily mediated by monocytes/macrophages, and once ruptured, both neutrophils, and a specific subset of inflammatory smooth muscle cells (SMCs) were involved in the process. The receiver operator characteristic curve (ROC) analysis indicated that distinct neutrophil subclusters were associated with IA formation and rupture, respectively. By reviewing current studies, we found that neutrophils play a detrimental role to IA wall integrity through secreting specific ligands, ferroptosis driven by ALOX5AP and PTGS2, and the formation of neutrophil extracellular traps (NETs) mediated by PADI4.InterpretationThis study delineated the biology and potential clinical implications of neutrophils in IA dome and provided a reliable basis for future researches.

show abstract

Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection

Cited by 65 publications

References 55 publications

JIB-04, a histone demethylase Jumonji C domain inhibitor, regulates phenotypic switching of vascular smooth muscle cells

JIB-04, a histone demethylase Jumonji C domain inhibitor, regulates phenotypic switching of vascular smooth muscle cells

Targeting Iron Metabolism and Ferroptosis as Novel Therapeutic Approaches in Cardiovascular Diseases

Decoding the biology and clinical implication of neutrophils in intracranial aneurysm

Contact Info

Product

Resources

About