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Ferroptosis is an iron-dependent regulated cell death driven by excessive lipid peroxidation. Inflammation is one common and effective physiological event that protects against various stimuli to maintain tissue homeostasis. However, the dysregulation of inflammatory responses can cause imbalance of the immune system, cell dysfunction and death. Recent studies have pointed out that activation of inflammation, including the activation of multiple inflammation-related signaling pathways, can lead to ferroptosis. Among the related signal transduction pathways, we focused on five classical inflammatory pathways, namely, the JAK-STAT, NF-κB, inflammasome, cGAS-STING and MAPK signaling pathways, and expounded on their roles in ferroptosis. To date, many agents have shown therapeutic effects on ferroptosis-related diseases by modulating the aforementioned pathways in vivo and in vitro. Moreover, the regulatory effects of these pathways on iron metabolism and lipid peroxidation have been described in detail, contributing to further understanding of the pathophysiological process of ferroptosis. Taken together, targeting these pathways related to inflammation will provide appropriate ways to intervene ferroptosis and diseases.

Prevention of neointima formation is the key to improving long‐term outcomes after stenting or coronary artery bypass grafting. RNA N6‐methyladenosine (m6A) methylation has been reported to be involved in the development of various cardiovascular diseases, but whether it has a regulatory effect on neointima formation is unknown. Herein, we revealed that methyltransferase‐like 3 (METTL3), the major methyltransferase of m6A methylation, was downregulated during vascular smooth muscle cell (VSMC) proliferation and neointima formation. Knockdown of METTL3 facilitated, while overexpression of METTL3 suppressed the proliferation of human aortic smooth muscle cells (HASMCs) by arresting HASMCs at G2/M checkpoint and the phosphorylation of CDC2 (p‐CDC2) was inactivated by METTL3. On the other hand, the migration and synthetic phenotype of HASMCs were enhanced by METTL3 knockdown, but inhibited by METTL3 overexpression. The protein levels of matrix metalloproteinase 2 (MMP2), MMP7 and MMP9 were reduced, while the expression level of tissue inhibitor of metalloproteinase 3 was increased in HASMCs with METTL3 overexpression. Moreover, METTL3 promoted the autophagosome formation by upregulating the expression of ATG5 (autophagy‐related 5) and ATG7. Knockdown of either ATG5 or ATG7 largely reversed the regulatory effects of METTL3 overexpression on phenotypic switching of HASMCs, as evidenced by increased proliferation and migration, and predisposed to synthetic phenotype. These results indicate that METTL3 inhibits the phenotypic switching of VSMCs by positively regulating ATG5‐mediated and ATG7‐mediated autophagosome formation. Thus, enhancing the level of RNA m6A or the formation of autophagosomes is the promising strategy to delay neointima formation. The expression of methyltransferase‐like 3 (METTL3) was inhibited by proliferation inducers in vascular smooth muscle cells (VSMCs). Overexpression of METTL3 promotes autophagy‐related 5 (ATG5) and ATG7 protein expression to facilitate autophagosome formation, which subsequently inhibits VSMC proliferation, migration and switching from contractile to synthetic phenotype. Knockdown of either ATG5 or ATG7 largely reversed the inhibitory effects of METTL3 on proliferation, migration and phenotypic switching of VSMCs. These findings indicate that METTL3 may inhibit neointima formation by accelerating the formation of autophagosomes.

Background E1A-associated 300-kDa protein (P300), an endogenous histone acetyltransferase, contributes to modifications of the chromatin landscape of genes involved in multiple cardiovascular diseases. Ferroptosis of vascular smooth muscle cells (VSMCs) is a novel pathological mechanism of aortic dissection. However, whether P300 regulates VSMC ferroptosis remains unknown. Methods Cystine deprivation (CD) and imidazole ketone erastin (IKE) were used to induce VSMC ferroptosis. Two different knockdown plasmids targeting P300 and A-485 (a specific inhibitor of P300) were used to investigate the function of P300 in the ferroptosis of human aortic smooth muscle cells (HASMCs). Cell counting kit-8, lactate dehydrogenase and flow cytometry with propidium iodide staining were performed to assess the cell viability and death under the treatment of CD and IKE. BODIPY-C11 assay, immunofluorescence staining of 4-hydroxynonenal and malondialdehyde assay were conducted to detect the level of lipid peroxidation. Furthermore, co-immunoprecipitation was utilized to explore the interaction between P300 and HIF-1α, HIF-1α and P53. Results Compared with normal control, the protein level of P300 was significantly decreased in HASMCs treated with CD and IKE, which was largely nullified by the ferroptosis inhibitor ferrostatin-1 but not by the autophagy inhibitor or apoptosis inhibitor. Knockdown of P300 by short-hairpin RNA or inhibition of P300 activity by A-485 promoted CD- and IKE-induced HASMC ferroptosis, as evidenced by a reduction in cell viability and aggravation of lipid peroxidation of HASMCs. Furthermore, we found that hypoxia-inducible factor-1α (HIF-1α)/heme oxygenase 1 (HMOX1) pathway was responsible for the impacts of P300 on ferroptosis of HASMCs. The results of co-immunoprecipitation demonstrated that P300 and P53 competitively bound HIF-1α to regulate the expression of HMOX1. Under normal conditions, P300 interacted with HIF-1α to inhibit HMOX1 expression, while reduced expression of P300 induced by ferroptosis inducers would favor HIF-1α binding to P53 to trigger HMOX1 overexpression. Furthermore, the aggravated effects of P300 knockdown on HASMC ferroptosis were largely nullified by HIF-1α knockdown or the HIF-1α inhibitor BAY87-2243. Conclusion Thus, our results revealed that P300 deficiency or inactivation facilitated CD- and IKE-induced VSMC ferroptosis by activating the HIF-1α/HMOX1 axis, which may contribute to the development of diseases related to VSMC ferroptosis.

SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2 (SMYD2) is a protein methyltransferase that methylates histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) and diverse nonhistone proteins. SMYD2 activity is required for normal organismal development and the regulation of a series of pathophysiological processes. Since aberrant SMYD2 expression and its dysfunction are often closely related to multiple diseases, SMYD2 is a promising candidate for the treatment of these diseases, such as cardiovascular disease and cancer. Here, we present an overview of the complex biology of SMYD2 and its family members and their context-dependent nature. Then, we discuss the discovery, structure, inhibitors, roles, and molecular mechanisms of SMYD2 in distinct diseases, with a focus on cardiovascular disease and cancer.

Enhancer of zeste homolog 2 (EZH2), a methyltransferase that di- and tri-methylates lysine-27 of histone H3, largely functions as a transcriptional repressor, and plays a critical role in various kinds of cancers. Here we report a novel function of EZH2 in regulating autophagic cell death (ACD) of vascular smooth muscle cells (VSMCs) that affect aortic dissection (AD). Inhibition of EZH2 activity by UNC1999 or knockdown EZH2 resulted in VSMC loss, while overexpression of EZH2 facilitated VSMC growth, and these effects of EZH2 on VSMCs were independent of proliferation and apoptosis. Interestingly, more autophagic vacuoles and increased LC3II protein levels were identified in VSMCs with EZH2 inhibition or deficiency. Moreover, when compared with counterparts, chloroquine alone, or chloroquine with rapamycin treatment led to more LC3II accumulation in EZH2 inhibited or knockdown VSMCs, which indicated that EZH2 negatively regulated autophagosome formation. In conjunction to this, ATG5 and ATG7 protein levels were remarkably increased in EZH2 inhibited or deficient VSMCs, and ATG5 or ATG7 knockdown virtually rescued VSMC loss induced by EZH2 inhibition or knockdown. In addition, we found that the MEK–ERK1/2 signaling pathway, but not AMPKα, mTOR, or AKT pathway, is responsible for the impact of EZH2 on ACD of VSMCs. Additionally, the adverse effects of EZH2 inhibition or knockdown on VSMCs were largely reversed by PD98059, an inhibitor of MEK1. More importantly, decreased EZH2 expression levels in the aortic wall of patients with AD indicated its contribution to VSMC loss and AD occurrence. Overall, these findings revealed that EZH2 affects ACD of VSMCs and the pathologic process of AD via regulating ATG5 and ATG7 expression and MEK–ERK1/2 signaling. Our hitherto unrecognized findings indicate that EZH2 activation has therapeutic or preventive potential for AD.

Background Metabolic dysregulation in patients with diabetes mellitus (DM) may contribute to pulmonary vascular remodeling, yet biomarkers for pulmonary hypertension (PH) risk in diabetes remain unclear. Objectives To assess the association between DM and incident PH, quantify mediation by circulating metabolites, and develop a metabolite-based PH risk model in diabetes. Methods In a prospective cohort of 459,714 UK Biobank participants without PH at baseline, Cox proportional hazard models estimated the association between DM and incident PH. Nuclear magnetic resonance (NMR) metabolomics, mediation analysis, and LASSO regression were used to identify metabolic mediators and construct a predictive model. Results During a median follow-up of 13.25 years, 2,250 PH cases occurred. DM was associated with a 39.6% higher PH risk (HR = 1.396, 95%CI:1.255–1.553; P  < 0.001), and earlier DM onset was associated with stronger risk ( P  < 0.001). Seven NMR-derived metabolites—related to hyperglycemia, inflammation (glycoprotein acetyls), amino acid and lipid metabolism—mediated 37.26% of the total effect. Including these metabolites improved prediction in diabetes (C index from 0.692 to 0.735; P  < 0.001). Conclusions DM is an independent risk factor for PH. Integration of NMR-derived metabolites improves risk prediction and suggests hyperglycemia and inflammation as key mechanisms, supporting the role of metabolomics in PH stratification and prevention among diabetes.

Background The pathological features of aortic dissection (AD) include vascular smooth muscle cell (VSMC) loss, elastic fiber fraction, and inflammatory responses in the aorta. However, little is known about the post-translational modification mechanisms responsible for these biological processes. Methods A total of 72 aorta samples, used for protein detection, were collected from 36 coronary artery disease (CAD, served as the control) patients and 36 type A AD (TAAD) patients. Chromatin immunoprecipitation (ChIP)-PCR was used to identify the genes regulated by H3K23ac, and tubastatin A, an inhibitor of HDAC6, was utilized to clarify the downstream mechanisms regulated by HDAC6. Results We found that the protein level of histone deacetylase HDAC6 was reduced in the aortas of patients suffering from TAAD and that the protein levels of H4K12ac, and H3K23ac significantly increased, while H3K18ac, H4K8ac, and H4K5ac dramatically decreased when compared with CAD patients. Although H3K23ac, H3K18ac, and H4K8ac increased in the human VSMCs after treatment with the HDAC6 inhibitor tubastatin A, only H3K23ac showed the same results in human tissues. Notably, the results of ChIP-PCR demonstrated that H3K23ac was enriched in extracellular matrix (ECM)-related genes, including Col1A2, Col3A1, CTGF, POSTN, MMP2, TIMP2, and ACTA2, in the aortic samples of TAAD patients. In addition, our results showed that HDAC6 regulates H4K20me2 and p-MEK1/2 in the pathological process of TAAD. Conclusions These results indicate that HDAC6 is involved in human TAAD formation by regulating H3K23ac, H4K20me2 and p-MEK1/2, thus, providing a strategy for the treatment of TAAD by targeting protein post-translational modifications (PTMs), chiefly histone PTMs.

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.

IntroductionMitral valve disease (MVD), including mitral valve regurgitation (MR) and mitral valve stenosis (MS), is a chronic and progressive cardiac malady. However, the metabolic alterations in MVD is not well-understood till now. The current gold standard diagnostic test, transthoracic echocardiography, has limitations on high-throughput measurement and lacks molecular information for early diagnosis of the disease.ObjectiveThe present study aimed to investigate the biochemical alterations and to explore their diagnostic potential for MVD.MethodsPlasma metabolic profile derangements and their diagnostic potential were non-invasively explored in 34 MR and 20 MS patients against their corresponding controls, using high-throughput NMR-based untargeted metabolomics.ResultsEighteen differential metabolites were identified for MR and MS patients respectively, on the basis of multivariate and univariate data analysis, which were mainly involved in energy metabolism, amino acid metabolism, calcium metabolism and inflammation. These differential metabolites, notably the significantly down-regulated formate and lactate, showed high diagnostic potential for MVD by using Spearman’s rank-order correlation analysis and ROC analysis.ConclusionsTo the best of our knowledge, the present study is the first one that explores the metabolic derangements and their diagnostic values in MVD patients using metabolomics. The findings indicated that metabolic disturbance occurred in MVD patients, with plasma formate and lactate emerged as important candidate biomarkers for MVD.

The behavior of vascular smooth muscle cells (VSMCs) contributes to the formation of neointima. We previously found that EHMT2 suppressed autophagy activation in VSMCs. BRD4770, an inhibitor of EHMT2/G9a, plays a critical role in several kinds of cancers. However, whether and how BRD4770 regulates the behavior of VSMCs remain unknown. In this study, we evaluate the cellular effect of BRD4770 on VSMCs by series of experiments in vivo and ex vivo. We demonstrated that BRD4770 inhibited VSMCs’ growth by blockage in G2/M phase in VSMCs. Moreover, our results demonstrated that the inhibition of proliferation was independent on autophagy or EHMT2 suppression which we previous reported. Mechanistically, BRD4770 exhibited an off-target effect from EHMT2 and our further study reveal that the proliferation inhibitory effect by BRD4770 was associated with suppressing on SUV39H2/KTM1B. In vivo, BRD4770 was also verified to rescue VIH. Thus, BRD4770 function as a crucial negative regulator of VSMC proliferation via SUV39H2 and G2/M cell cycle arrest and BRD4770 could be a molecule for the therapy of vascular restenosis.