Aortic diseases are often clinically silent until advanced stages, and risk determinants beyond traditional cardiovascular factors remain incompletely characterised. Here, we investigate associations of 42 chronic conditions and multimorbidity with incident aortic disease in UK Biobank (UKB), with external validation in China Kadoorie Biobank (CKB). In UKB, 21 chronic conditions are associated with overall aortic disease after false discovery rate correction, including coronary heart disease, hypertension, atrial fibrillation, peripheral vascular disease, heart failure, and COPD; similar patterns are observed in CKB. Aortic atherosclerosis shows the broadest comorbidity profile, whereas dissection and aneurysm subtypes show narrower profiles. Higher multimorbidity burden is associated with higher incidence in both cohorts. In UKB, hypertension shows the largest estimated population-attributable fraction, with additional contributions from COPD and chronic kidney disease. Mendelian randomization supports selected associations, and machine-learning models show internal discriminatory performance. These findings support consideration of multimorbidity in aortic disease risk assessment.

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. To assess the association between DM and incident PH, quantify mediation by circulating metabolites, and develop a metabolite-based PH risk model in diabetes. 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. During a median follow-up of 13.25 years, 2,250 PH cases occurred. DM was associated with a 39.6

Aortic dissection (AD) is a fatal emergency which lacks effective drug therapies. Previous studies demonstrated that histone deacetylase 8 (HDAC8) inhibition provides protective benefits in several cardiovascular diseases, including heart failure, fibrosis, and cardiac hypertrophy. However, the role of HDAC8 in AD remains unclear. In the present study, we investigated the function of PCI-34051, a highly selective inhibitor of HDAC8, in human aortic smooth muscle cell (HASMC) ferroptosis and β-aminopropionitrile (BAPN)-induced AD in mice. The results showed that PCI-34051 and HDAC8 knockdown significantly inhibited cystine deprivation (CD)- and imidazole ketone erastin (IKE)-induced HASMC ferroptosis, as evidenced by an increase in cell viability, reduction in cell injury/death, and lipid peroxidation levels in HASMCs. Transcriptome sequencing analysis revealed that the anti-ferroptosis effect of PCI-34051 was associated with the regulation of activator protein-1 (AP-1). Additionally, co-immunoprecipitation results showed that HDAC8 interacts with c-JUN, a component of AP-1. Overexpression of AP-1 (c-FOS and c-JUN) largely abolished the inhibitory effects of PCI-34051 on HASMC ferroptosis. More importantly, PCI-34051 reduced BAPN-induced AD incidence and aortic rupture mortality in mice by inhibiting HASMC ferroptosis and inflammatory response. Taken together, inhibition of HDAC8 by PCI-34051 may provide a preventive or therapeutic strategy for AD by attenuating HASMC ferroptosis.

Minimally invasive coronary artery bypass grafting (MICS CABG) via an anterolateral mini-thoracotomy represents a viable and safe approach. However, the proximal anastomosis of the saphenous vein to the ascending aorta can be technically challenging, particularly in cases with a prominent right ventricular outflow tract or pulmonary artery. In this report, we present an enhanced proximal anastomosis technique for minimally invasive coronary artery bypass grafting performed via intercostal thoracotomy. 45 patients with a mean age of 64.6 ± 9.0 years underwent minimally invasive coronary artery bypass grafting with enhanced technique via intercostal thoracotomy between July 2021 and November 2023. Multilevel pericardial retractions were employed to laterally displace the heart and a flexible side-biting clamp was placed on the ascending aorta via a 1-cm incision in the left second intercostal space, enabling handsewn proximal anastomoses on the ascending aorta. The mean number of grafts was 2.8 ± 0.5, with a total of 11 patients (24

Pulmonary arterial hypertension (PAH) poses a growing global health challenge, yet comprehensive epidemiological data remain limited. This study aims to assess the burden of PAH from 1990 to 2021 and project trends to 2040, addressing critical gaps in incidence, mortality, and disability-adjusted life years (DALYs) across diverse socio-demographic contexts. Using data from the Global Burden of Disease (GBD) 2021 study, we analyzed PAH burden across 204 countries and territories, stratified by age, sex, region, and socio-demographic index (SDI). Age-standardized rates (per 100,000 populations) for incidence (ASIR), mortality (ASMR), and DALYs (ASDR) were calculated. Future trends were projected via a Bayesian age-period-cohort (BAPC) model. In 2021, there were 43,251 (95

Cardiac fibrosis contributes to adverse cardiac remodeling and loss of heart function eventually leading to heart failure (HF). Resident cardiac fibroblasts are the principal source of myofibroblasts that produce extracellular matrix proteins to mediate cardiac fibrosis. We report that TET3 depletion in cultured cardiac fibroblasts blocked transition to myofibroblasts in response to different pro-fibrogenic stimuli. Consistently, deletion of TET3 from quiescent or activated fibroblast (myofibroblast) attenuated cardiac fibrosis and rescued heart function in mice. Importantly, a small-molecule TET3-specific degrader Bobcat339 displayed therapeutic potential by mitigating cardiac fibrosis and normalizing heart function when administered post-surgery. Integrated transcriptomic analysis identified the mechanosensor Piezo2 as a downstream target for TET3. Piezo2 inhibition dampened fibroblast activation in vitro and ameliorated cardiac fibrosis in vivo. Mechanistically, Piezo2 promoted fibroblast activation by modulating the activities of mechanosensitive transcription factors. Finally, relevance of TET3 and Piezo2 was verified in heart specimens collected from HF patients. In conclusion, our data demonstrate that TET3 is a pivotal regulator of cardiac fibrosis and can be potentially targeted for the intervention of heart failure.

BACKGROUND AND AIMS:Mitochondrial dynamics are key mechanism regulating the conversion of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype, which is involved in neointima formation and restenosis. However, the underlying mechanisms leading to mitochondrial dysfunction are not fully understood. METHODS:Western blot was used to detect the expression of relevant molecules at the protein level. CCK-8, EdU assays, and transwell were used to test cell proliferation and migration capacity. Flow cytometry was used to assess cell cycle and ROS. RESULTS:AK4 was upregulated in 10 % fetal bovine serum (FBS)- and 20 ng/mL platelet-derived growth factor-BB (PDGF-BB)-induced human aortic VSMCs (HASMCs). Knockdown of AK4 suppressed the proliferation and synthetic phenotype of HASMCs, while AK4 overexpression accelerated it. Mechanistically, AK4 interacted with protein kinase AMP-activated catalytic subunit alpha (AMPKα) and promoted the phosphorylation of AMPKα at Thr172, which reduced mitochondrial oxidative damage and improved mitochondrial function. Furthermore, activation of AMPKα by metformin or AICAR (acadesine) reversed the inhibitory effects of AK4 deficiency on HASMC phenotypic switching. Moreover, overexpression of wild-type AMPKα counteracted the effects of AK4 knockdown, whereas mutational inactivation of AMPKα (AMPKαT172A) was not effective in reversing the effect on HASMCs. CONCLUSIONS:Our findings suggest that AK4 is a novel regulator of AMPKα activity and positively regulates VSMC dedifferentiation, proliferation, and migration. Targeted inhibition of AK4 may be a potential approach for the treatment of neointima formation and restenosis.

Myocardial infarction (MI) is a life-threatening cardiovascular disease that, on average, results in 8.5 million deaths worldwide each year. Timely revascularization of occluded vessels is a critical method of myocardial salvage. However, reperfusion paradoxically leads to the worsening of myocardial damage known as myocardial ischaemia/reperfusion injury (MI/RI). Therefore, reducing the size of myocardial infarction after reperfusion is critical and remains an important therapeutic goal. The susceptibility of the myocardium to MI/RI may be increased by diabetes. Currently, some traditional antidiabetic agents such as metformin reduce MI/RI by decreasing inflammation, inhibiting oxidative stress, and improving vascular endothelial function. This appears to be a new direction for the treatment of MI/RI. Recent cardiovascular outcome trials have shown that several oral antidiabetic agents, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4is), and sodium-glucose-linked transporter-2 inhibitors (SGLT-2is), not only have good antidiabetic effects but also have a protective effect on myocardial protection. This article aims to discuss the mechanisms and effects of oral antidiabetic agents, including GLP-1RAs, DPP-4is, and SGLT-2is, on MI/RI to facilitate their clinical application.

Aims: Vascular smooth muscle cell (VSMC) ferroptosis is a pivotal event in the process of aortic dissection (AD), and a number of agents have a protective role against AD by inhibiting VSMC ferroptosis. While glycolysis is an ancient pathway related to almost all biological processes, its precise involvement in VSMC ferroptosis and AD remains unclear. Results: In this study, bioinformatics analysis revealed that glycolysis-related molecules and pathways were involved in VSMC ferroptosis and AD. We focused on the key enzyme of glycolysis, lactate dehydrogenase A (LDHA), and found that LDHA overexpression promoted ferroptosis and lipid peroxidation in cystine deprivation- or imidazole ketone erastin-treated VSMCs and vice versa. Clinical specimens showed a negative correlation between elevated LDHA levels in dissected aortae and ferroptosis-related molecules glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and ferroptosis suppressor protein 1 (FSP1). In VSMC ferroptosis, LDHA overexpression led to the suppression of GPX4, SLC7A11, and FSP1. Furthermore, the interaction between LDHA and nuclear factor (erythroid-derived 2)-like 2 (NRF2) was identified, and the overexpression or agonist of NRF2 reversed the contribution of LDHA on VSMC ferroptosis and lipid peroxidation. Innovation and Conclusion: These results highlight a significant association between LDHA and VSMC ferroptosis in AD development mediated through NRF2. These findings present LDHA as a potential target for AD intervention by inhibiting its expression. Antioxid. Redox Signal. 42, 378-392.

BACKGROUND:Hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs) and consequent pulmonary vascular remodeling are the crucial pathological features of pulmonary hypertension (PH). Protein methylation has been shown to be critically involved in PASMC proliferation and PH, but the underlying mechanism remains largely unknown. METHODS:PH animal models were generated by treating mice/rats with chronic hypoxia for 4 weeks. SMYD2-vTg mice (vascular smooth muscle cell-specific suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 (deformed epidural auto-regulatory factor-1) domain-containing protein 2 transgenic) or wild-type rats and mice treated with LLY-507 (3-cyano-5-{2-[4-[2-(3-methylindol-1-yl)ethyl]piperazin-1-yl]-phenyl}-N-[(3-pyrrolidin-1-yl)propyl]benzamide) were used to investigate the function of SMYD2 (suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 domain-containing protein 2) on PH development in vivo. Primary cultured rat PASMCs with SMYD2 knockdown or overexpression were used to explore the effects of SMYD2 on proliferation and to decipher the underlying mechanism. RESULTS:We demonstrated that the expression of the lysine methyltransferase SMYD2 was upregulated in the smooth muscle cells of pulmonary arteries from patients with PH and hypoxia-exposed rats/mice and in the cytoplasm of hypoxia-induced rat PASMCs. More importantly, targeted inhibition of SMYD2 by LLY-507 significantly attenuated hypoxia-induced pulmonary vascular remodeling and PH development in both male and female rats in vivo and reduced rat PASMC hyperproliferation in vitro. In contrast, SMYD2-vTg mice exhibited more severe PH phenotypes and related pathological changes than nontransgenic mice after 4 weeks of chronic hypoxia treatment. Furthermore, SMYD2 overexpression promoted, while SMYD2 knockdown suppressed, the proliferation of rat PASMCs by affecting the cell cycle checkpoint between S and G2 phases. Mechanistically, we revealed that SMYD2 directly interacted with and monomethylated PPARγ (peroxisome proliferator-activated receptor gamma) to inhibit the nuclear translocation and transcriptional activity of PPARγ, which further promoted mitophagy to facilitate PASMC proliferation and PH development. Furthermore, rosiglitazone, a PPARγ agonist, largely abolished the detrimental effects of SMYD2 overexpression on PASMC proliferation and PH. CONCLUSIONS:Our results demonstrated that SMYD2 monomethylates nonhistone PPARγ and inhibits its nuclear translocation and activation to accelerate PASMC proliferation and PH by triggering mitophagy, indicating that targeting SMYD2 or activating PPARγ are potential strategies for the prevention of PH.

Coronary restenosis is an important cause of poor long-term prognosis in patients with coronary heart disease. Here, we show that lysine methyltransferase SMYD2 expression in the nucleus is significantly elevated in serum- and PDGF-BB-induced vascular smooth muscle cells (VSMCs), and in tissues of carotid artery injury-induced neointimal hyperplasia. Smyd2 overexpression in VSMCs (Smyd2-vTg) facilitates, but treatment with its specific inhibitor LLY-507 or SMYD2 knockdown significantly inhibits VSMC phenotypic switching and carotid artery injury-induced neointima formation in mice. Transcriptome sequencing revealed that SMYD2 knockdown represses the expression of serum response factor (SRF) target genes and that SRF overexpression largely reverses the inhibitory effect of SMYD2 knockdown on VSMC proliferation. HDAC3 directly interacts with and deacetylates SRF, which enhances SRF transcriptional activity in VSMCs. Moreover, SMYD2 promotes HDAC3 expression via tri-methylation of H3K36 at its promoter. RGFP966, a specific inhibitor of HDAC3, not only counteracts the pro-proliferation effect of SMYD2 overexpression on VSMCs, but also inhibits carotid artery injury-induced neointima formation in mice. HDAC3 partially abolishes the inhibitory effect of SMYD2 knockdown on VSMC proliferation in a deacetylase activity-dependent manner. Our results reveal that the SMYD2-HDAC3-SRF axis constitutes a novel and critical epigenetic mechanism that regulates VSMC phenotypic switching and neointimal hyperplasia.

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.

目的 观察2例肺移植术后肺动脉狭窄患者的临床表现,总结治疗经验.方法 回顾性分析2021年1月-2022年12月郑州大学第一附属医院肺移植术后发生肺动脉狭窄2例患者的临床资料.例1在体外膜肺氧合下行左单肺移植术,例2在体外膜肺氧合下先行右肺移植术再行左肺移植术,2例术后均常规给予免疫抑制、抗感染、抗凝及营养支持等治疗.结果 例1左肺移植术后第7天大便后出现胸闷,指脉氧饱和度迅速降至84％,平卧位吸氧后胸闷缓解,指脉氧饱和度升至99％;之后患者静息状态一般情况可,下床稍剧烈活动即出现胸闷气喘,考虑右心衰竭及肺部感染,经加强抗感染、强心、利尿等对症治疗,症状稍缓解;术后第36天行肺动脉CT血管造影,示左肺动脉干狭窄,于肺移植术后第64天行肺动脉球囊扩张术,症状缓解,但次日再次出现胸闷气喘;于肺移植术后第84天行左肺动脉干支架植入术后胸闷症状缓解;肺移植术后第119天出院,恢复基本正常生活;随访1年以上无胸闷表现.例2双肺移植术后第6天床旁站立突发呼吸、心脏骤停,予以气管插管并于右侧股动静脉建立体外膜肺氧合;术后第10天患者血流动力学稍稳定情况下行肺动脉CT血管造影,示双侧肺动脉狭窄并多发动脉栓塞形成,给予抗凝、溶栓等支持治疗;术后第25天发生感染性休克,术后第31天自动出院.结论 肺移植术后出现活动后胸闷气喘,排除心力衰竭、肺部感染、气道病变等后应考虑肺动脉狭窄可能,行肺动脉血管造影检查明确肺动脉狭窄后根据患者情况行药物或肺动脉球囊扩张术、肺动脉支架植入术手术治疗.

目的 探讨胎儿先天性肺囊腺瘤样畸形(congenital cystic adenomatoid malformation,CCAM)发病的危险因素,为CCAM预防提供依据.方法 产前行三维彩超发现胎儿CCAM的孕妇104例为CCAM组,未发现肺部相关病变胎儿的孕妇96例为对照组,比较2组年龄、孕次及妊娠早期过敏史、感冒史、服药史、甲醛吸入史、吸烟史、饮酒史,胎儿父亲吸烟史、饮酒史比率.采用多因素logistic回归分析胎儿CCAM发病的影响因素;绘制ROC曲线,评估孕妇年龄、孕次、妊娠早期服药史预测胎儿CCAM发病的效能.结果 CCAM组年龄[(28.58±4.12)岁]小于对照组[(30.12±4.57)岁](t=-2.504,P=0.013),孕次[2(1,2)次]多于对照组[1(1,2)次](U=-2.279,P=0.023),妊娠早期服药史比率(47.12％)高于对照组(25.00％)(x2=10.534,P=0.001),妊娠早期过敏史、感冒史、甲醛吸入史、吸烟史、饮酒史及胎儿父亲吸烟史、饮酒史比率与对照组比较差异均无统计学意义(P＞0.05).孕妇年龄(OR=0.892,95％CI:0.829～0.959,P=0.002)、孕次(OR=1.592,95％CI:1.046～2.422,P=0.030)、妊娠早期服药史(OR=2.645,95％CI:1.386～5.034,P=0.003)是胎儿CCAM发病的影响因素.年龄、孕次分别以31.5岁、1.5次为最佳截断值,预测胎儿CCAM 发病的 AUC 分别为 0.605(95％CI:0.526～0.683,P=0.011)、0.583(95％CI:0.504～0.663,P=0.042),灵敏度分别为38.5％、64.6％,特异度分别为78.8％、53.8％;妊娠早期服药史预测胎儿CCAM发病的AUC为0.611(95％CI:0.532～0.689,P=0.007),灵敏度为75.0％,特异度为47.1％;三者联合预测胎儿CCAM发病的AUC为0.695(95％CI:0.621～0.768,P＜0.001),灵敏度为56.2％,特异度为77.9％.结论 孕妇年龄小、孕次多、妊娠早期服药可增加胎儿CCAM发病风险,孕妇年龄、孕次、妊娠早期服药史三者联合预测胎儿CCAM发病有一定价值.

目的 观察间质性肺炎患者肺移植术后30 d生存情况,探讨其围术期死亡的影响因素.方法 回顾性分析2020年1月-2022年12月郑州大学第一附属医院行肺移植术治疗的52例间质性肺炎患者临床资料.52例中术后30 d存活者44例为存活组,死亡者8例为死亡组.比较2组术前pa(CO2)、氧合指数、肺动脉压、血乳酸、中性粒细胞与淋巴细胞比值、血红蛋白、脑钠肽、气道真菌感染、气道细菌感染、CT血管造影异常情况,供肺冷缺血时间、手术时间、失血量、输血量、双肺移植及术中体外膜肺氧合比率,术后pa(CO2)、48 h氧合指数、肺动脉压、血乳酸、中性粒细胞与淋巴细胞比值、血红蛋白、脑钠肽、C反应蛋白、降钙素原及气道真菌感染、气道细菌感染、气道并发症发生率.多因素logistic回归分析间质性肺炎患者肺移植术后30 d死亡的影响因素.结果 死亡组术前pa(CO2)[58.1(40.3,79.7)mmHg]、血乳酸[1.7(1.1,1.9)mmol/L]及术后气道并发症(62.5％)、气道细菌感染(100.0％)发生率均高于存活组[45.0(37.0,50.2)mmHg、1.0(0.8,1.2)mmol/L、18.2％、61.4％](P＜0.05),2组性别比例,年龄,体质量指数,合并高血压、糖尿病、脑梗死、心脏病比率,有吸烟、饮酒史比率,术前肺动脉压、氧合指数、中性粒细胞与淋巴细胞比值、血红蛋白、脑钠肽、血乳酸及气道真菌感染、气道细菌感染、CT血管造影异常比率,供肺冷缺血时间、手术时间、失血量、输血量及双肺移植、术中体外膜肺氧合比率,术后pa(CO2)、48 h氧合指数、肺动脉压、中性粒细胞与淋巴细胞比值、血红蛋白、血乳酸、脑钠肽、C反应蛋白、降钙素原及气道真菌感染比率比较差异均无统计学意义(P＞0.05).术前pa(CO2)(OR=1.127,95％CI:1.022～1.242,P=0.016)、术前血乳酸(OR=7.541,95％CI:1.111～51.159,P=0.039)是间质性肺炎患者肺移植术后30 d死亡的影响因素.结论 术前pa(CO2)、血乳酸水平升高的间质性肺炎患者肺移植术后30 d死亡风险增加.

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.

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. 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. 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. 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.

目的 分析1例特发性肺纤维化合并酒精性肝硬化失代偿期行肝肺联合移植术患者的临床资料,探讨其临床治疗效果.方法 患者于体外膜肺氧合辅助下先行左肺移植术,后行肝移植术.肺移植吻合顺序为左主支气管、左肺动脉、左侧左房袖;肝移植吻合顺序为肝上下腔静脉、肝下下腔静脉、门静脉、肝动脉、胆总管-胆总管端端吻合.肺动脉开放前予以巴利昔单抗、甲泼尼龙琥珀酸钠诱导免疫;术后鼻饲他克莫司、吗替麦考酚酯,静脉注射甲泼尼龙琥珀酸钠.结果 患者术后64 h撤离体外膜肺氧合;术后第4天撤离呼吸机并下床活动;术后第10天出现不明原因的顽固性低氧血症,行气管切开、呼吸机辅助呼吸及肺动脉球囊扩张,低氧血症仍存在,拟行右肺移植术;术后第21天肺泡灌洗液培养出大肠埃希氏菌、嗜麦芽窄食单胞菌、烟曲霉;术后第32天因感染性休克、心脏骤停死亡.结论 终末期肝脏、肺部疾病患者可行肝肺联合移植术;严格选择供体、进一步优化手术流程、尽可能双肺移植是该病例带来的经验教训;应用体外肺灌注技术改善供体质量、延长器官保存时间,是未来发展的方向.

Prevention of neointima formation is the key to improving long-term outcomes after stenting or coronary artery bypass grafting. RNA N6 -methyladenosine (m6 A) 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 m6 A 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 m6 A or the formation of autophagosomes is the promising strategy to delay neointima formation.