It is well known that aortic dissection (AD) is a very aggressive class of vascular diseases. S-adenosylmethionine (SAM) is an autophagy inhibitor with anti-inflammatory and anti-oxidative stress effects; however, the role of SAM in AD is unknown. In this study, we constructed an animal model of AD using subcutaneous minipump continuous infusion of AngII-induced ApoE-/-mice and a cytopathic model using AngII-induced primary vascular smooth muscle cells (VSMCs) to investigate the possible role of SAM in AD. The results showed that mice in the AngII + SAM group had significantly lower AD incidence, significantly prolonged survival, and reduced vascular elastic fiber disruption compared with mice in the AngII group. In addition, SAM significantly inhibited autophagy in vivo and in vitro. Meanwhile, SAM also inhibited the cellular phenotypic switch, mainly by up regulating the expression levels of contractile marker proteins [α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α)] and down regulating the expression levels of synthetic marker proteins [osteoblast protein (OPN), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9)]. Molecularly, SAM inhibited AD formation mainly by activating the PI3K/AKT/mTOR signaling pathway. Using a PI3K inhibitor (LY294002) significantly reversed the protective effect of SAM in AngII-induced mice and VSMCs.Our study demonstrates the protective effect of SAM on mice under AngII-induced AD for the first time. SAM prevented AD formation mainly by inhibiting cellular phenotypic switch and autophagy, and activation of the PI3K/AKT/mTOR signaling pathway is a possible molecular mechanism. Thus, SAM may be a novel strategy for the treatment of AD.

Neointimal hyperplasia is a major clinical complication of coronary artery bypass graft and percutaneous coronary intervention. Smooth muscle cells (SMCs) play a vital roles in neointimal hyperplasia development and undergo complex phenotype switching. Previous studies have linked glucose transporter member 10(Glut10) to the phenotypic transformation of SMCs. In this research, we reported that Glut10 helps maintain the contractile phenotype of SMCs. The Glut10-TET2/3 signaling axis can arrest neointimal hyperplasia progression by improving mitochondrial function via promotion of mtDNA demethylation in SMCs. Glut10 is significantly downregulated in both human and mouse restenotic arteries. Global Glut10 deletion or SMC-specific Glut10 ablation in the carotid artery of mice accelerated neointimal hyperplasia, while Glut10 overexpression in the carotid artery triggered the opposite effects. All of these changes were accompanied by a significant increase in vascular SMCs migration and proliferation. Mechanistically, Glut10 is expressed primarily in the mitochondria after platelet-derived growth factor-BB (PDGF-BB) treatment. Glut10 ablation induced a reduction in ascorbic acid (VitC) concentrations in mitochondria and mitochondrial DNA (mtDNA) hypermethylation by decreasing the activity and expression of the Ten-eleven translocation (TET) protein family. We also observed that Glut10 deficiency aggravated mitochondrial dysfunction and decreased the adenosinetriphosphate (ATP) content and the oxygen consumption rate, which also caused SMCs to switch their phenotype from contractile to synthetic phenotype. Furthermore, mitochondria-specific TET family inhibition partially reversed these effects. These results suggested that Glut10 helps maintain the contractile phenotype of SMCs. The Glut10-TET2/3 signaling axis can arrest neointimal hyperplasia progression by improving mitochondrial function via the promotion of mtDNA demethylation in SMCs.

Acute rejection may manifest following heart transplantation, despite the implementation of relatively well-established immunosuppression protocols. The significance of the mTOR signaling pathway in rejection is widely acknowledged. BEZ235, a second-generation mTOR inhibitor with dual inhibitory effects on PI3K and mTOR, holds promise for clinical applications. This study developed a nanodelivery system, BEZ235@NP, to facilitate the intracellular delivery of BEZ235, which enhances efficacy and reduces adverse effects by improving the poor solubility of BEZ235. In the complete MHCII-mismatched model, BEZ235@NP significantly prolonged cardiac allografts survival compared to free BEZ235, which was attributed to more effective suppression of effector T cell activation and promotion of greater expansion of Tregs. These nanoparticles demonstrated excellent biosafety and exhibited no short-term biotoxicity upon investigation. To elucidate the mechanism, primary T cells were isolated from the spleen and it was observed that BEZ235@NP treatment resulted in the arrest of these cells in the G0/G1 phase. As indicated by Western blot analysis, BEZ235@NP substantially reduced mTOR phosphorylation. This, in turn, suppressed downstream pathways and ultimately exerted an anti-proliferative and anti-activating effect on cells. Furthermore, it was observed that inhibition of the mTOR pathway stimulated T-cell autophagy. In conclusion, the strategy of intracellular delivery of BEZ235 presents promising applications for the treatment of acute rejection.

Background: Aortic dissection (AD) is a macrovascular disease which is pathologically characterized by aortic media degeneration (AMD). Our team's previous research found that iron deficiency (ID) promoted the formation of AMD through presentative research. In this study, we aimed to investigate the underlying mechanism of ID promoting AMD formation. Methods: The human aortic tissues were harvested from AD patients and organ donors. ApoE-/- mice were simultaneously given AngII infusion and low-iron feed to investigate the relationship between ID and AD. The IRE1-XBP1-CHOP signal axis of endoplasmic reticulum (ER) stress was selectively inhibited with 4μ8C. Iron contents were detected by Perls staining. The expression of iron metabolism and ER stress-relative proteins were analyzed by IF and western blotting. Apoptosis rates of aortic tissue and ASMCs were detected by TUNEL staining and flow cytometry, and ROS content was also measured by the flow cytometry. Results: ID was accompanied by ER stress in patients with AD. Among the three signaling pathways of ER stress in ID-induced AMD, proteins of IRE1, PERK and ATF6 signaling pathways were up-regulated by 2.65 times, 1.14 times and 1.24 times, respectively. ID was positively related to ER stress, mitochondrial oxidative stress and aortic media apoptosis in vivo and in vitro assays, while 4μ8C reversed the severity of ER stress and AMD. Conclusions: ID could activate ER stress by eliciting mitochondrial oxidative stress to activate the IRE1-XBP1-CHOP signaling pathway in the ER, which accelerated the apoptosis of ASMCs in aortic media, thus promoting the formation of AMD.

Iron deficiency (ID) is a global nutritional deficiency that was shown to be involved in the pathogenesis of aortic aneurysm and dissection (AAD) in our previous studies. Some studies suggested that mitochondrial dynamics was involved in the apoptosis and phenotypic transformation of vascular smooth muscle cells (VSMCs). However, little is known about the role of mitochondrial dynamics in aortic medial degeneration (AMD) promoted by an iron deficient diet. The present study investigated the effect of ID on the phenotypic transformation of VSMCs, the progression of AMD, and the underlying mechanism. The expression of p-Drp1 (Ser616) and Fis1 was markedly upregulated in the aortic media of AAD patients and ApoE(-/-) mice with subcutaneous AngII osmotic pumps. ID facilitated the formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), which triggered excessive mitochondrial fission, induced the phenotypic transformation of VSMCs, and ultimately accelerated the progression of AMD. Furthermore, the present study indicated that an inhibitor of Drp1 could partially reverse this process. Maintaining iron balance in the human body may prevent the development of AAD.

人工心脏的发展及临床应用给终末期心脏病患者的治疗带来了希望 [1] ,也对原位心脏移植提出了更高要求。目前国际心脏移植数量不断增加,我国每年进行原位心脏移植术约400余例,临床效果与国际相当。伴随移植领域器官保护、围手术期处理以及免疫抑制剂的发展,心脏移植临床效果也得到进一步提高。2015年6月至2019年4月,武汉大学人民医院连续成功行70例单纯原位心脏移植无院内死亡,取得良好的临床效果,现总结经验如下。

主动脉夹层(AD)及主动脉动脉瘤(AA)均属于心血管危重症,病理特点为主动脉中膜退行性变(AMD).AMD主要病理生理机制为主动脉壁中膜弹力纤维断裂,血管平滑肌细胞(VSMC)表型转化,细胞外基质(ECM)降解,VSMC增殖迁移增加、凋亡增多导致主动脉结构和功能薄弱[1].本文对AMD研究的常用生物学检测指标及检验技术作一综述.

Objective:A retrospective analysis of 7 patients who died after heart transplantation in a single center, and to explore the risk factors for death after heart transplantation.Methods:From May 1, 2015 to May 1, 2019, 74 cases of orthotopic heart transplantation were performed in the Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University. By April 2020, with a follow-up time of 724 days, 65 recipients survived and 9 died. Two cases of death due to non-medical causes were excluded, and the recipients were divided into survival group (65 cases) and death group (7 cases). Preoperative, intraoperative, and postoperative parameters and corresponding donor conditions were collected for the survival group. Continuous variables that met the normal distribution were compared using the t-test, and continuous variables that were not normally distributed were analyzed using the Kruskal-Wallis test. Enumeration data were compared using Fisher′s exact test. Survival curves were plotted using the Kaplan-Meier method. Cox proportional hazards models were used to analyze risk factors for death after heart transplantation.Results:Of the 7 dead recipients, 4 died of transplant heart failure, rejection, respiratory failure and other organ failure during hospitalization, including 1 recipient of combined heart-lung transplantation and 3 recipients who died during follow-up: 2 cases with poor compliance with immunosuppressive agents, 1 case with transplant heart failure, rejection and liver failure. There were no significant differences in age at operation, body mass index, left ventricular ejection fraction, primary disease, preoperative cardiopulmonary resuscitation, vasoactive drug maintenance and ECMO transition between the surviving recipients (P>0.05). There were no significant differences in donor age, poor body weight, donor cold ischemia time, cause of brain death, donor/recipient sex and ABO blood group matching, and marginal donor ratio in the death and survival groups (P>0.05), and the proportion of donor/recipient age difference (>17 years) in the death group was higher than that in the survival group (P<0.05). The median cardiopulmonary bypass time was 201 (185, 226) and 170 (152, 197) min, the intraoperative packed red blood cell dosage was 8.0 (5.5, 9.0) and 4.0 (2.0, 6.0) U, and the platelet dosage was 4.0 (2.0, 6.0) and 2.0 (2.0, 2.0) U in the surviving recipients, and the differences were statistically significant (P<0.05). The ICU stay and postoperative ventilator use time of recipients in the death group were longer than those in the survival group, 11.1 (5.9, 17.7) and 3.8 (2.9-5.0) d, 58 (12, 172) and 8 (6, 15) h, respectively; meanwhile, the proportion of recipients who stayed in the ICU (stay >5 d) and used the ventilator for a long time (use > 24 h) in the death group was higher than that in the survival group, and the differences were statistically significant (P<0.05 for all). The 1-, 3-, and 5-year overall survival rates of the 74 recipients were 91.9%, 84.7%, and 74.1%, respectively. The factors with statistically significant differences in preoperative and intraoperative indicators and corresponding donor indicators between the two groups were included in Cox proportional hazards model analysis. The results showed that intraoperative platelet dosage was an independent risk factor for death after heart transplantation. For every U increase in intraoperative platelet use, the risk of postoperative death increased by 1.35 times (HR=2.35, 95% CI 1.28~4.32, P<0.05).Conclusions:The outcome after heart transplantation is influenced by many factors. Excessive differences in intraoperative red blood cell and platelet dosage and donor/recipient age are risk factors for death after heart transplantation.

Despite decades of study into aortic dissection (AD), a lethal cardiovascular emergency due to a tear in the aorta intima or bleeding within the aortic wall, leading to the separation of the different layers of it, the factors that influence its progression and the deeper regulatory mechanisms remain poorly understood. Nowadays, with the maturity of N6-methyladenosine (m6A) sequence technology, m6A modification, one type of RNA epigenesis, has gradually become a new research hotspot for epigenetic molecular regulation. Especially recently, increasing evidence has revealed that m6A modification functions as a pivotal post-transcriptional modification to influence the progression of multiple diseases. Based on these findings, it is reasonable to speculate that m6A modification may affect the onset and progression of AD. To explore the validity of our conjecture and to elucidate its underlying molecular mechanism of action, we conducted the present study. In this study, we found that KIAA1429 is downregulated while ALKBH5 is upregulated in aortic tissues from AD patients. Furthermore, gain- and loss-of-function studies showed that KIAA1429 and ALKBH5 can oppositely regulate HASMC proliferation, HAEC apoptosis, and AD progression in AngII-infused mice. Mechanistically, we demonstrated that KIAA1429/ALKBH5-mediated m6A modifications can regulate the processing of pri-miR-143-3p through interacting with the microprocessor protein DGCR8, thus indirectly regulating the downstream target gene of mature miR-143-3p, DDX6, to perform their biological functions in vitro and in vivo. Our findings have revealed a novel connection between m6A modification and AD progression and may provide a novel molecular basis for subsequent researchers to search for novel therapeutic approaches to improve the health of patients struggling with AD.

Recently, mounting evidence indicates that N6-methyladenosine (m6A) modification functions as a pivotal posttranscriptional modification that regulates noncoding RNA biogenesis to influence the progression of multiple diseases. However, whether m6A modification is involved in aortic dissection (AD) development has never been reported. Meanwhile, numerous studies have shown that AngII-induced inflammatory damage and excessive apoptosis of human aortic smooth muscle cells (HASMCs) are the crucial pathological features of AD development. Therefore, in this study, we intended to explore whether m6A modification can regulate AD progression by influencing the damage effects of AngII on HASMCs and elucidate the underlying mechanisms. Firstly, we screened and confirmed the high expression of alkylation repair homolog protein 5 (ALKBH5), a key m6A demethylase, in aortic tissues from AD patients, indicating that m6A modification may indeed be involved in AD progression. Subsequently, we demonstrated that ALKBH5 can exacerbate the AngII-induced HASMC inflammatory injury as well as apoptosis and shorten the survival time of AngII-infused mice. Mechanistically, we revealed that lncRNA TMPO-AS1 is a downstream target for ALKBH5 to affect AD progression in vitro and vivo. Meanwhile, we confirmed that ALKBH5-mediated m6A demethylation downregulates lnc-TMPO-AS1 by decreasing the stability of its nascent. Further, we demonstrated that lnc-TMPO-AS1 exhibits its functions in HASMCs, at least partly, through downregulating IRAK4 at the epigenetic level by combining with EZH2. Finally, the direct positive correlation between ALKBH5 and IRAK4 in terms of the expression level and biological function was confirmed, which further enforced the preciseness and correctness of our findings. In conclusion, our study demonstrated that ALKBH5 aggravates AD by promoting inflammatory response and apoptosis of HASMCs via regulating lnc-TMPO-AS1/EZH2/IRAK4 signals in an m6A modification manner and may provide a novel molecular basis for subsequent researchers to searching for novel therapeutic approaches to improve the health of patients fighting AD and other cardiovascular diseases.

Objective:To retrospectively analyze the experience of our center in the use of marginal donor heart, and to explore the principle of use and risk control of marginal donor heart.Methods:A total of 31 patients with end-stage heart disease underwent orthotopic heart transplantation in our center from January 2018 to December 2018, including 28 cases of pure heart transplantation, 2 cases of combined heart-lung transplantation, and 1 case of combined heart-kidney transplantation. 26 of the 31 cases were marginal donor hearts. These patients were all anastomosed by a double lumen method.Results:The rates of postoperative use of ECMO, IABP and acute rejection were zero in this study. The time of cardiopulmonary bypass in the marginal donor group was significantly longer compared with the conventional donor group( P<0.05), but there was no significant difference between the two groups in terms of hospitalization time, mechanical ventilation time, ICU stay time, abnormal rate of ECG, LVEF and blood biochemical indexes(all P>0.05). The postoperative follow-up rate was 100% in the two groups. One case of combined heart-lung transplantation in the marginal donor group died of multiple organ failure in the first month after surgery. During the postoperative follow-up period, the incidence of moderate to severe tricuspid regurgitation and the incidence of recurrent heart failure were zero in the two groups. There was no significant difference in the incidence of arrhythmia, LVEF, infection and blood biochemical parameters. Conclusion:The application of marginal donor heart has no significant effect on the short-term survival rate and recovery of patients after heart transplantation, but the long-term effect needs further follow-up.

Our aim was to investigate the effect of avβ3 single-stranded DNA aptamer (avβ3 ssDNA) on vascular restenosis in rats after percutaneous transluminal coronary angioplasty (PTCA) via the Ras-PI3K/MAPK pathway. Sixty Sprague-Dawley rats were randomly divided into six groups: sham-operated, PTCA, PTCA+cilengitide (18 mg/kg, n = 8), and avβ3 ssDNA treatment at 50, 100, and 200 μg/kg. Hematoxylin-eosin staining was performed to evaluate the successful establishment of the PTCA model and to assess the degree of intimal hyperplasia. Immunofluorescence and in situ hybridization were carried out to observe the level of avβ3. Immunohistochemistry was used to detect the expression of E-cadherin, N-cadherin, α-smooth muscle actin (α-SMA), angiotensin 1 (ANG1), and ANG2. The expression of osteopontin (OPN), focal adhesion kinase (FAK), Ras, mitogen-activated protein kinase (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), signal transducer and activator of transcription 1 (STAT1), and GTPase was observed by the western blot and quantitative reverse transcription polymerase chain reaction. Compared with rats subjected to PTCA only, those treated with avβ3 ssDNA showed significantly decreased vascular occlusion rate (P < .05). The protein expression of avβ3, OPN, p-FAK, ANG2, and E-cadherin was significantly increased by avβ3 ssDNA (P < .05), while the levels of ANG1, α-SMA, N-cadherin Ras, MAPK, PI3K, STAT1, and GTPase were significantly decreased (P < .05). Avβ3 ssDNA reduced the proliferation, migration, epithelial-mesenchymal transition, and vascular remodeling of vascular smooth muscle cells, and the mechanism may be related to the Ras-PI3K/MAPK pathway.

Objective:To construct a diagnostic model for prognosis of lung adenocarcinoma and digging the diagnostic value of the model.Methods:Data was downloaded from the Cancer Genome Atlas. The search deadline is April 10, 2020. Differentially expressed micro-RNAs (DEMs) between lung adenocarcinoma tissues ( n=515) and adjacent tissues ( n=46) were screened out by using likelihood ratio test. The correlation between DEMsand prognosis of patients by univariate Cox regression analysis and robust likelihood-based survival analysis was used to find the most reliable microRNA (miRNAs, miR). Multivariate Cox regression analysis was used to construct a risk-score model. After finding the best cut-off point on the receiver operating characteristic (ROC) curve, the patients were divided into high-and low-risk groups, and the survival curves were carried out to judge the diagnostic effect of the model in different data sets. Results:257 DEMs were screened out. A total of 12 miRNAs which were strongly correlated with the prognosis of patients were obtained [hazard ratio ( HR)=0.25, 0.08, 0.25, 0.04, 0.09, 0.004, 0.26, 0.22, 0.08, 0.01, 0.02, -0.09, χ2=13.85, 11.30, 7.54, 6.05, 5.76, 5.79, 4.85, 4.74, 4.66, 4.51, 4.25, 4.22, P<0.05]. The 12-miRNA risk-score model indicated the survivaltime of patients in high risk group ( n=131) is shorter than patients in low risk group ( n=130), which was 37.8 months and 77.8 months, respectively ( χ2=19.70, P<0.01). Using the the optimal cut-off point of 1.322 as the standard, the training group, the testing group and the overall group were divided into high ( n=80, 95, 176) and low ( n=180, 166, 346) risk groups respectively. The 12-miRNA model can still distinguish the survival time of each group (high risk=15.5, 31.7, 29.9 months, low risk= 59.7, 55.1, 59.7 months, χ2=32.80, 8.40, 28.20, all P<0.01). Conclusion:The 12-miRNA risk-score model can provide a new way for the diagnosis of lung adenocarcinoma.

目的 分析主动脉夹层(AD)发病相关危险因素的流行病学特点,以指导临床诊治.方法 选择2017年1月～2019年6月我中心收治因胸痛就诊入院的患者733例,根据最终诊断,将确诊AD患者328作为病例组,非AD患者405例作为对照组,回顾性分析比较2组患者一般资料、既往病史和实验室指标,多因素logistic回归分析AD的影响因素.结果 与对照组比较,病例组高血压、动脉粥样硬化、马方综合征、白塞病、主动脉瓣二叶畸形、大动脉炎、吸烟、饮酒比例、TC、TG、LDL-C水平明显升高,载脂蛋白A-I和HDL-C水平明显降低(P＜0.05,P＜0.01).logistic回归分析显示,高血压(OR=5.334,95％CI:3.757～7.574,P=0.000)、马方综合征(OR=4.681,95％CI:2.893～7.576,P=0.000)、主动脉瓣二叶畸形(OR=2.365,95％CI:1.476～3.812,P=0.000)、吸烟(OR=1.908,95％CI:1.164～3.126,P=0.010),载脂蛋白A-I (OR =0.524,95％CI:0.320～0.859,P=0.010)和HDL-C(OR=0.187,95％CI:0.132～0.266,P=0.000)是AD的影响因素.结论 高血压、马方综合征、主动脉瓣二叶畸形、吸烟是AD的独立危险因素,栽脂蛋白A-I和HDL-C是AD发病的独立保护因素.

目的 总结不同杂交手术方式治疗急性Stanford A型主动脉夹层并分析临床效果.方法 回顾性分析21例Stanford A型主动脉夹层杂交手术,观察术中体外循环时间、术后治疗时间、术后并发症、出院后随访等相关指标.结果 术中体外循环时间(115±10.9)min,主动脉阻断时间(52±4.6)min,呼吸机辅助呼吸(15±3.2)h,监护室治疗(33±0.8)h,术后住院(14±1.9)d,术后并发症3例,21例患者术后均治愈出院,出院后随访结果良好.结论 杂交手术治疗急性Stanford A型主动脉夹层,避免了高风险的深低温停循环,甚至无需体外循环辅助,手术时间缩短,创伤小,术后恢复快,术后早期临床效果满意,是主动脉夹层传统手术的很好补充,远期效果仍需大样本和长期随访来进一步考证.

主动脉夹层(aortic dissection,AD)表现为主动脉内膜破裂,主动脉腔内的血液涌人中膜内,使中膜分离,沿长轴撕裂主动脉形成真假两腔.目前AD的发病机制尚未明确,前期研究发现,γ干扰素(interferon-γ,IFN-γ)在AD发病中起到了极其重要的作用.IFN-γ作为炎性因子能够诱导T淋巴细胞产生基质金属蛋白酶9(matrix metalloproteinase-9,MMP-9)[1-2].MMP-9可以破坏主动脉壁正常结构,引起主动脉扩张及破裂,导致AD发生[3-4].现对IFN-γ在AD发病机制中的作用作一综述.

目的 观察经食道超声引导下经胸微创房间隔缺损封堵术治疗继发孔中央型房间隔缺损的临床效果.方法 98例继发孔中央型房间隔缺损患者,均行经食道超声引导下经胸微创房间隔缺损封堵术治疗.观察患者围术期指标及术后并发症发生情况.结果 所有患者均顺利完成手术,手术时间(44.2±6.5)min,术后呼吸机辅助时间(232.2±57.3)min,ICU停留时间(16.2±7.5)h,术后住院时间(4.5±0.8)d,切口大小(4.4±0.9)cm,胸腔引流液(67.6±11.2)ml.术后发生心律失常4例,出血1例,肺不张1例,无残余分流、封堵器脱落、移位及死亡病例.患者术后肺动脉压力及纽约心脏病协会心功能分级均低于术前(均P<0.05).结论 经食道超声引导下经胸微创房间隔缺损封堵术治疗继发孔中央型房间隔缺损疗效确切,安全性高,可有效改善患者心功能.