Coronary artery bypass grafting (CABG) reconstructs the blood supply for treating coronary heart disease. One of the most used conduits is the great saphenous vein, but its effect is limited, owing to lower long-term patency versus arterial grafts. This study devised a 3D bio-printed stent, comprising of genetically modified human bone marrow mesenchymal stem cells (BMSCs), to improve venous graft patency. BMSCs and endothelial cells (ECs) were obtained from sternal bone marrow and discarded saphenous veins, respectively. BMSCs were transduced with lentivirus overexpressing sirtuin-3 (SIRT3) and seeded on a 3D bio-printed matrix stent, comprising of hyaluronic acid methacryloyl and gelatin methacryloyl (HAMA/GelMA). A rat CABG model was established, via generating a jugular vein-common carotid artery arteriovenous graft. The SIRT3-BMSC-seeded stent was “wrapped” around this venous graft, serving as an extravascular stent. An in vitro model was also devised, in which lipopolysaccharide (LPS)-pre-treated ECs were co-cultured with SIRT3-BMSCs, followed by evaluating mitochondrial transferal and tunneling nanotube (TNT) formation-related functional changes. Immunoprecipitation was used to examine SIRT3-vasodilator-simulated phosphoprotein (VASP) interactions. Rat arteriovenous graft model found that SIRT3-BMSC+stent, compared to Control, Stent, and BMSC+stent groups, had the greatest graft vessel diameter, maximum blood flow velocity during systole and CD31+ EC area, along with the lowest cell proliferation and inflammatory cell infiltration; therefore, SIRT3-BMSC+stent had the greatest inhibitory effects on venous graft neointimal formation. In vitro, LPS-pre-treated ECs, after co-culture with SIRT3-BMSCs, restored endothelial, along with lowering mesenchymal marker expression. Furthermore, mechanistic analyses revealed increased SIRT-BMSC-to-LPS-pre-treated EC mitochondrial transfer, facilitated by TNTs formed between SIRT3-BMSCs and ECs. This mitochondrial transfer was mediated via SIRT3-VASP interactions, in which SIRT3 deacetylates VASP to promote TNT. SIRT3-BMSC/HAMA/GelMA extravascular stent could effectively lower arteriovenous graft dilation and inhibit neointimal formation, possibly via SIRT3 deacetylation of VASP, thereby promoting TNT formation, and subsequently, mitochondrial transfer from BMSCs to ECs to improve EC function. Thus, the extravascular stent was able to provide external support, along with facilitating BMSC therapeutic effects.

Ventricular remodeling (VR) associated with hypertension (HTN) is characterized by a complex molecular mechanism. In the context of clinical treatment, substantial challenges persist. A total of 12 differentially expressed genes were jointly obtained from different cohorts and weighted gene co-expression network analysis (WGCNA). Among them, genes associated with oxidative stress were screened out. Upon verification through learning machine, it was revealed that NR1H2 and MT1E are closely associated with the progression of HTN-VR. Their stability was validated using both internal and external datasets. The study presented the immune cell infiltration patterns associated with these key genes and the potential mechanisms underlying disease progression, which were further verified in mouse models. The research revealed that NR1H2 and MT1E serve as crucial risk markers for the progression of HTN and VR. These efforts are intended to offer valuable insights into the underlying mechanisms and uncover potential targets for clinical intervention.

The transplantation of human bone marrow mesenchymal stem cells (hMSCs) exhibits promising therapeutic effects in the treatment of myocardial infarction (MI), however, its clinical application is limited due to the low survival rate of the transplanted cells. Three-dimensional (3D) bioprinted tissue engineering patches have demonstrated efficacy as a delivery approach to enhance the viability and engraftment of stem cells. In this study, we have developed a novel hMSCs tissue-engineered patch equipped with a nano-slow-release system using 3D bioprinting technology. The patch is based on a matrix material consisting of methacrylated gelatin (GelMA) and chitosan nanoparticles loaded with vascular endothelial growth factor (VEGF), which possesses pro-angiogenic effects. The resulting patch demonstrated excellent compatibility with hMSCs and enabled stable, sustained VEGF release.In vivoresults showed that the patch significantly reduced cardiomyocyte apoptosis three days after MI, and improved cardiac function and myocardial fibrosis at 28 d post-surgery. These effects were closely associated with the patch's potent angiogenic properties and favorable stem cell survival. In conclusion, this study successfully developed a 3D-printed tissue engineering patch with strong potential for clinical application, offering a promising new approach for the treatment of MI.

Myocardial ischemia-reperfusion (MI/R) injury limits the therapeutic effects of revascularization in acute myocardial infarction. In this study, we investigated whether human SIRT3 (hSIRT3) and TIMP3 (hTIMP3) could achieve targeted delivery with the assist of cationic microbubbles (CMBs) and a synergistic protection effect on porcine MI/R myocardium. Firstly, CMBs carrying the hSIRT3 or hTIMP3 plasmids were used individually or synergistically for cardiac-targeted delivery in MI/R pigs. After 7 days of observation, hSIRT3 and hTIMP3 were mainly enriched in myocardium, especially in the infarction center, without additional increase in cTNI and pathological damage to non-cardiac organs. At the same time, hSIRT3 and hTIMP3 exerted a protective role against myocardial injury, as gene therapy significantly inhibited myocardial apoptosis, inflammation and oxidative damage. After 90 days of observation, hSIRT3 and hTIMP3 application exerted an inhibiting effect on development of heart failure, as the strategy significantly increased the density of vascular, and limited the myocardial fibrosis, area scar size, the decline of cardiac function. As expected, collaborative applications of hSIRT3 and hTIMP3 showed a better protective effect than hSIRT3 or hTIMP3 application alone. Collectively, hSIRT3 and hTIMP3 delivered with CMBs in heart could exert positive effect on myocardial protection after MI/R in pigs.

Aging is a significant risk factor for cardiovascular diseases, with ischemic heart disease (IHD) being the leading cause of cardiovascular-related mortality. Inhibition of FOXO4, which selectively eliminates senescent cells, offers protective effects on the aging myocardium. However, the removal of senescent cells may lead to a reduction in tissue cell density, thereby exacerbating tissue space formation and perivascular fibrosis. Therefore, selectively eliminating senescent cells in the aging heart, while simultaneously replenishing therapeutic bone marrow-derived mesenchymal stem cells (BMSCs), holds substantial therapeutic potential for synergistically combating cardiac aging. This study proposes a promising cardiac rejuvenation strategy using ultrasound-targeted microbubble destruction (UTMD)-mediated delivery of shFOXO4/SDF1 to eliminate cellular senescence and enhance BMSC homing. Transcriptomic analysis identified FOXO4 as a pivotal transcription factor in cardiac aging, with FOXO4 protein predominantly expressed in cardiac fibroblasts (CFs) and vascular endothelial cells in the myocardium of aged rats. Knockdown of FOXO4 in aging CFs reversed cellular senescence, and co-culturing these rejuvenated CFs with BMSCs further enhanced the reversal of senescence and bolstered resistance to oxidative stress. The use of UTMD for delivering shFOXO4/SDF1 in dual-gene therapy significantly enhanced BMSC homing, ameliorating cardiac aging, oxidative stress, and inflammation. In an ischemia-reperfusion injury (MIRI) model, pretreatment with shFOXO4/SDF1 effectively reduced cardiomyocyte apoptosis, promoted neovascularization, reduced infarct size, and improved cardiac function. The combined removal of senescent cells and enhanced BMSC homing synergistically ameliorated cardiac aging and improved post-MIRI prognosis in aging hearts. These findings provide novel insights and potential therapeutic strategies for addressing cardiac aging and age-related heart diseases.

Background Dichloroacetate (DCA) has shown potential in modulating cellular metabolism and inflammation, particularly in cardiac conditions. This study investigates DCA's protective effects in a mouse model of myocardial infarction (MI), focusing on its ability to enhance cardiac function, reduce inflammation, and shift macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype. Methods An acute MI model was created using left anterior descending coronary artery ligation. Mice were assigned to four groups: normal control, MI control, MI + 50 mM DCA, and MI + 100 mM DCA. Cardiac fibrosis and injury were assessed through H&E staining. Cardiac function was evaluated via echocardiography, and serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were measured. Inflammation and apoptosis were analyzed through immunohistochemistry, ELISA, western blotting, and flow cytometry in heart tissue and RAW264.7 cells. Additionally, macrophage polarization and relevant signaling pathways were examined. Results DCA significantly improved cardiac function in MI mice, evidenced by reduced myocardial injury and lower CK-MB and LDH levels. It also decreased inflammatory cytokines (TNF-α, IL-6 and IL-1β) and facilitated macrophage polarization from M1 to M2. Western blotting revealed that DCA inhibited iNOS and COX2 while enhancing Arg1 expression, alongside improved mitochondrial function and reduced apoptosis. Additionally, by injecting AAV-PDHK4 (pyruvate dehydrogenase kinase) into MI mice, we found that DCA effectively inhibited the progression of MI through the suppression of PDHK4. Conclusion DCA protects against myocardial infarction by enhancing cardiac function, reducing inflammation, and promoting macrophage polarization, likely through inhibition of PDHK4 and NF-κB pathways, positioning it as a potential therapeutic strategy for cardiac repair post-MI.

Objective: Valves replacement is the only strategy for aortic valve stenosis (AVS) treatment. A comprehensively understanding about pathogenesis of AVS would be helpful for individualized treatment of AVS in the future. Methods: The mRNA profiles of Normal and AVS samples were harvested from the Gene Expression Omnibus database. The differently expressed genes (DEGs) were identified via limma package. Among the DEGs, the least absolute shrinkage and selection operator (LASSO) logistic regression and random forest (RF) analysis were utilized to identify the biomarkers for AVS. Cibersort package were used to assess the difference of infiltration levels of 22 types of immune cells between Normal and AVS groups. Besides, the most significant immune cell was also evaluated by RF analysis. The relationships between the identified biomarkers and immune cells were assessed via correlation analysis. Set Enrichment Analysis (GSEA) of single genes was conducted to reveal the potential mechanisms involved by the biomarkers. And the DGIdb database was utilized for the drug prediction for the crucial biomarkers. Results: There was a total of 543 DEGs including 315 up-regulated and 228 down-regulated DEGs. Among them, CXCL5, COL4A3 and EPB41L4B were the significant biomarkers of AVS. The T cells CD4 memory resting and activated, plasma cells, M0 macrophages, T cells regulatory (Tregs) and neutrophils were the significantly infiltrative immune cells in which neutrophils was the most important immune cell type in AVS. CXCL5 could regulate all significantly infiltrative immune cells involved in AVS development, while COL4A3 and EPB41L4B only mediated the neutrophils in AVS. Moreover, ECM receptor interaction, focal adhesion, chemokine signaling pathways and insulin signaling pathway were the main mechanisms involved by the biomarkers. Collagenase clostridium histolyticum and Ocriplasmin was the potential drug for COL4A3. Conclusion: The infiltration of neutrophils mediated by CXCL5, COL4A3, and EPB41L4B may be a pivotal mechanism of AVS.

Background:Acute Stanford Type A Aortic Dissection (ATAAD) is a critical medical emergency characterized by significant morbidity and mortality. This study aims to identify specific gene expression patterns and RNA modification associated with ATAAD. Methods:The GSE153434 dataset was obtained from the Gene Expression Omnibus (GEO) database. Differential expression analysis was conducted to identify differential expression genes (DEGs) associated with ATAAD. To validate the involvement of RNA modification in ATAAD, RNA modification-related genes (M6A, M1A, M5C, APA, A-to-I) were acquired from GeneCards, following by Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. A gene prediction signature consisting of key genes was established, and Real-time PCR was used to validate the gene expression in clinical samples. The patients were then divided into high and low-risk groups, and subsequent enrichment analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and assessments of immune infiltration. A co-expression network analysis (WGCNA) was performed to explore gene-phenotype relationships and identify key genes. Results:A total of 45 RNA modification genes were acquired. Six gene signatures (YTHDC1, WTAP, CFI, ADARB1, ADARB2, TET3) were developed for ATAAD diagnosis and risk stratification. Enrichment analysis suggested the potential involvement of inflammation and extracellular matrix pathways in the progression of ATAAD. The incorporation of pertinent genes from the GSE147026 dataset into the six-gene signature further validated the model's effectiveness. A significant upregulation in WTAP, ADARB2, and TET3 expression, whereas YTHDC1 exhibited a noteworthy downregulation in the ATAAD group. Conclusion:Six-gene signature could serve as an efficient model for predicting the diagnosis of ATAAD.

Long non-coding RNA LINC01214 is reported to be up-regulated in non-small cell lung cancer (NSCLC), however, its function in NSCLC has not been elucidated yet. In our study, we verified that LINC01214 was aberrantly higher in the tumor tissues and cell lines than that in the normal controls, and was relevant to the severity and prognosis of NSCLC through using real-time quantitative PCR. Then, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide assay and flow cytometry illustrated that knocking down LINC01214 restrained cell proliferation and promoted apoptosis in A549 and H1299 cells. Additionally, western blot results confirmed that LINC01214 silence reduced the protein expression of CDK2, CDK6, CyclinD1 and Bcl2, but increased the protein expression of Bax and Caspase-3. Of note, compared to normal cells, NSCLC cells had higher enrichment level of N6-methyladenosine (m6A) modification of LINC01214, while reducing m6A modification of LINC01214 weakened the stability of LINC01214 and diminished its level in A549 and H1299 through down-regulating methyltransferase METTL3 or overexpressing demethylase ALKBH5. Subsequently, molecular experiments proved that LINC01214 acted as a sponge for miR-195-5p to elevate ROCK1 expression in NSCLC. Furthermore, data from functional recovery experiments showed that elevating miR-195-5p also exerted tumor-suppressive effects in NSCLC; meanwhile, the effects were reversed by overexpressing ROCK1 or inhibiting miR-195-5p. In short, m6A modification-mediated up-regulation of LINC01214 advances cell proliferation and tumorigenesis to promote NSCLC progression through inhibiting miR-195-5p to up-regulate ROCK1.

Gene therapy has received great attention as a therapeutic approach to improve cardiac function post-myocardial infarction (MI), but its limitation lies in the lack of targeting. This study explored the use of ultrasound-targeted microbubble destruction (UTMD) technique to deliver β-catenin gene to the myocardium, aiming to evaluate its efficacy in preventing cardiac dysfunction post-MI. A cationic microbubble solution containing β-catenin gene pcDNA3.1 plasmid was injected through the tail vein at a rate of 0.6 mL/h, and ultrasound beams were delivered to the heart using GE Vivid 7 Medical Ultrasound System M3s Transducer. Bioluminescence imaging was used to analyze the efficiency of UTMD gene transfection into the myocardium. β-catenin levels were detected by real-time polymerase chain reaction and western blot. Additionally, MI was induced in mice by surgical ligation of the left coronary artery, and cardiac function was evaluated using echocardiography at 14 and 28 days post-surgery. Masson’s trichrome staining was employed to determine infarct size. Blood vessel density was also measured. TUNEL assay was used to measure cardiomyocyte apoptosis. Furthermore, mouse cardiac stem cells were isolated using flow cytometry, and Giemsa stain was applied to evaluate the colony adhesion. UTMD delivered the gene to the heart with high efficiency and specificity in vivo. The β-catenin expression was significantly increased in the myocardium (P < 0.01). After MI, the β-catenin group exhibited a notable improvement in the gene therapy-induced neovascularization in the border zone (P < 0.01) and the number and function of cardiac stem cells (P < 0.01), and a significant decrease in cardiomyocyte apoptosis in the heart tissue (P < 0.01). β-catenin gene pre-treated with UTMD can reduce the impact of myocardial injury and promote cardiac self-repair after MI.

ExplorationVolume 4, Issue 3 20240302 BACK COVEROpen Access Back Cover: Ion cocktail therapy for myocardial infarction by synergistic regulation of both structural and electrical remodeling (EXP2 3/2024) Yumei Que, Yumei QueSearch for more papers by this authorJiaxin Shi, Jiaxin ShiSearch for more papers by this authorZhaowenbin Zhang, Zhaowenbin ZhangSearch for more papers by this authorLu Sun, Lu SunSearch for more papers by this authorHairu Li, Hairu LiSearch for more papers by this authorXionghai Qin, Xionghai QinSearch for more papers by this authorZhen Zeng, Zhen ZengSearch for more papers by this authorXiao Yang, Xiao YangSearch for more papers by this authorYanxin Chen, Yanxin ChenSearch for more papers by this authorChong Liu, Chong LiuSearch for more papers by this authorChang Liu, Chang LiuSearch for more papers by this authorShijie Sun, Shijie SunSearch for more papers by this authorQishu Jin, Qishu JinSearch for more papers by this authorYanxin Zhang, Yanxin ZhangSearch for more papers by this authorXin Li, Xin LiSearch for more papers by this authorMing Lei, Ming LeiSearch for more papers by this authorChen Yang, Chen YangSearch for more papers by this authorHai Tian, Hai TianSearch for more papers by this authorJiawei Tian, Jiawei TianSearch for more papers by this authorJiang Chang, Jiang ChangSearch for more papers by this author Yumei Que, Yumei QueSearch for more papers by this authorJiaxin Shi, Jiaxin ShiSearch for more papers by this authorZhaowenbin Zhang, Zhaowenbin ZhangSearch for more papers by this authorLu Sun, Lu SunSearch for more papers by this authorHairu Li, Hairu LiSearch for more papers by this authorXionghai Qin, Xionghai QinSearch for more papers by this authorZhen Zeng, Zhen ZengSearch for more papers by this authorXiao Yang, Xiao YangSearch for more papers by this authorYanxin Chen, Yanxin ChenSearch for more papers by this authorChong Liu, Chong LiuSearch for more papers by this authorChang Liu, Chang LiuSearch for more papers by this authorShijie Sun, Shijie SunSearch for more papers by this authorQishu Jin, Qishu JinSearch for more papers by this authorYanxin Zhang, Yanxin ZhangSearch for more papers by this authorXin Li, Xin LiSearch for more papers by this authorMing Lei, Ming LeiSearch for more papers by this authorChen Yang, Chen YangSearch for more papers by this authorHai Tian, Hai TianSearch for more papers by this authorJiawei Tian, Jiawei TianSearch for more papers by this authorJiang Chang, Jiang ChangSearch for more papers by this author First published: 18 June 2024 https://doi.org/10.1002/EXP.20240302AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Ion cocktail consisting of silicate, strontium and copper ions significantly reduces the deteriorative electrical and structural remodeling after myocardial infarction by stimulating angiogenesis of endothelial cells and M2 polarization of macrophages, and inhibiting cardiomyocyte apoptosis under hypoxia/ischemic condition. This ion cocktail therapy reveals a new strategy to effectively treat myocardial infarction with clinical translation potential. Volume4, Issue3June 202420240302 RelatedInformation

Myocardial infarction (MI) is a leading cause of death worldwide. Few drugs hold the ability to depress cardiac electrical and structural remodeling simultaneously after MI, which is crucial for the treatment of MI. The aim of this study is to investigate an effective therapy to improve both electrical and structural remodeling of the heart caused by MI. Here, an "ion cocktail therapy" is proposed to simultaneously reverse cardiac structural and electrical remodeling post-MI in rats and minipigs by applying a unique combination of silicate, strontium (Sr) and copper (Cu) ions due to their specific regulatory effects on the behavior of the key cells involved in MI including angiogenesis of endothelial cells, M2 polarization of macrophages and apoptosis of cardiomyocyte. The results demonstrate that ion cocktail treatment attenuates structural remodeling post-MI by ameliorating infarct size, promoting angiogenesis in both peri-infarct and infarct areas. Meantime, to some extent, ion cocktail treatment reverses the deteriorative electrical remodeling by reducing the incidence rate of early/delayed afterdepolarizations and minimizing the heterogeneity of cardiac electrophysiology. This ion cocktail therapy reveals a new strategy to effectively treat MI with great clinical translation potential due to the high effectiveness and safety of the ion cocktail combination.

3D打印是指通过数字图像数据转换为具有三维物理模型的技术.随着3D打印技术的不断成熟并与医学领域的结合,3D生物打印为心血管疾病治疗康复提供新思路.本文就3D生物打印技术在心血管领域研究的进展作一综述.

Bone marrow mesenchymal stem cell (BMSC) transplantation is an effective treatment for ischemic heart disease, but its effectiveness is limited in aging populations due to decreased viability and injury resistance of autologous BMSCs. The purpose of this study was to compare the differences between platelet-rich plasma (PRP) derived from young and aged donors, and to investigate whether it is possible to enhance the viability of elderly human BMSCs (hBMSCs) using PRP, and to apply the rejuvenated hBMSCs for the treatment of ischemia. The key growth factors in PRP, including IGF-1, EGF, and PDGF-BB, were found to have significant differences between young and old individuals. Our results showed that PRP could enhance the proliferation, cloning, and rejuvenation of aged hBMSCs, with a superior effect observed when using PRP derived from younger donors. In the SD rat infarct model, the application of hBMSCs optimized with PRP resulted in a smaller infarct area compared to the control group (NC-Old). Specifically, the infarct area in the group treated with hBMSCs cultured with PRP from young donors (YPRP-Old) was smaller than that in the group treated with PRP from older donors (OPRP-Old). The survival rate of hBMSCs after transplantation, the number of neovascularization in the infarct area of SD rats and the recovery of cardiac function were all higher in the YPRP-Old group than the OPRP-Old group, and both groups were better than the group treated with aged hBMSCs alone. In conclusion, PRP may provide a new stem cell transplantation therapy option for ischemic diseases.

Cardiac fibrosis is a common pathological cardiac remodeling in a variety of heart diseases, characterized by the activation of cardiac fibroblasts.Our previous study uncovered that promyelocytic leukemia protein (PML)-associated SUMO processes is a new regulator of cardiac hypertrophy and heart failure.The present study aimed to explore the role of PML in cardiac fibroblasts activation.Here we found that PML is significantly upregulated in cardiac fibrotic tissue and activated cardiac fibroblasts treated with transforming growth factor-β1 (TGF-β1).Gain-and loss-of-function experiments showed that PML impacted cardiac fibroblasts activation after TGF-β1 treatment.Further study demonstrated that p53 acts as the transcriptional regulator of PML, and participated in TGF-β1 induced the increase of PML expression and PML nuclear bodies (PML-NBs) formation.Knockdown or pharmacological inhibition of p53 produced inhibitory effects on the activation of cardiac fibroblasts.We further found that PML also may stabilize p53 through inhibiting its ubiquitin-mediated proteasomal degradation in cardiac fibroblasts.Collectively, this study suggests that PML crosstalk with p53 regulates cardiac fibroblasts activation, which provides a novel therapeutic strategy for cardiac fibrosis.

"微创"是现代心脏外科的重要发展趋势,胸腔镜下的心脏外科手术虽然近年来刚刚起步,但却是心脏外科领域一次非常重要的"微创"技术飞跃,也是微创心脏手术未来发展的重要方向.胸腔镜下的心脏外科手术与传统手术相比较具有损伤小、恢复快、美观等特点,但对心脏外科医师所需要掌握的心脏外科胸腔镜技术要求较高.

Background: Acute Stanford type A aortic dissection (ATAAD) is a potentially fatal outcome of cardiac surgery with a high mortality rate and an unclear pathogenesis. This study aimed to investigate the prospective diagnostic biomarkers and molecular pathways in ATAAD.Methods: We identified autophagy-related differentially expressed genes (DEGs) between control ATAAD groups using three Gene Expression Omnibus (GEO) datasets (GSE153434, GSE98770, and GSE52093). The potential pathways and biomark-ers were then determined through protein-protein interaction (PPI) network and enrichment analysis. The autophagy-related hub genes and their corresponding diagnostic values were determined using receiver operating characteristic analysis and the significant immune-associated pathways were identified using Gene-Set Variation Analysis (GSVA) enrichment.Results: A total of 90 genes were screened as autophagy-related DEGs and 10 hub genes were ultimately identified using a PPI network in patients with ATAAD. Autophagy-related DEGs were enriched in pathways related to autophagy, protein binding, regulation of autophagy, and the relaxin signaling pathway according to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Gene-set enrichment analysis suggested that the regulation of autophagosome assembly, focal adhesion, and calcium-signaling pathways are enriched mainly in ATAAD development. In addition, GSVA showed that DEGs in ATAAD are primarily involved in the metabolic pathways of myocardial diseases and autophagy. Finally, it was found that the immune infiltration between the control and ATAAD groups was significantly different.Conclusions: Through the comprehensive analysis of GEO data, our study provides insights into autophagy-related biomarkers and therapeutic targets to diagnose and treat patients who are susceptible to ATAAD.

BACKGROUND:Thoracic aortic aneurysm (TAA) occurs due to pathological aortal dilation, and both individuals with normal tricuspid aortic valves (TAV) or abnormal bicuspid aortic valves (BAV), the latter being a congenital condition, are at risk. However, some differences are present between TAA/BAV and TAA/TAV with respect to their pathophysiological processes and molecular mechanisms, but their exact nature is still mostly unknown. Therefore, it is necessary to elucidate TAA developmental differences among BAV vs. TAV patients.METHODS:Publically-available gene expression datasets, aortic tissue derived from TAA/BAV and TAA/TAV individuals, were analyzed by weighted gene co-expression network analysis (WGCNA) to identify gene modules associated with those conditions. Gene Ontology (GO) enrichment analysis was performed on those modules to identify the enriched genes within those modules, which were verified by Gene Set Variation Analysis (GSVA) on a dataset derived from aortic smooth muscle cell gene expression between TAA/TAV and TAV/BAV patients. Immune cell infiltration patterns were then analyzed by CIBERSORT, and a protein-protein interaction (PPI) network was constructed based on WGCNA and enrichment analysis results to identify hub genes, followed by validation via stepwise regression analysis. Three signatures most strongly associated with TAA/TAV were confirmed by receiver operating characteristic (ROC) and decision curve analyses (DCA) between prior-established training and testing gene sets.RESULTS:WGCNA delineated 2 gene modules being associated with TAA/TAV vs. TAA/BAV; both were enriched for immune-associated genes, such as those relating to immune responses, etc., under enrichment analysis. TAA/TAV and TAA/BAV tissues also had differing infiltrating immune cell proportions, particularly with respect to dendritic, mast and CD4 memory T cells. Identified three signatures, CD86, integrin beta 2 (ITGB2) and alpha M (ITGAM), as yielding the strongest associations with TAA/TAV onset, which was verified by areas under the curve (AUC) at levels approximating 0.8 or above under ROC analysis, indicating their predictive value for TAA/TAV onset. However, we did not examine possible confounding variables, so there are many alternative explanations for this association.CONCLUSIONS:TAA/TAV pathogenesis was found to be more associated with immune-related gene expression compared to TAA/BAV, and the identification of three strongly-associated genes could facilitate their usage as future biomarkers for diagnosing the likelihood of TAA/TAV onset vs. TAA/BAV, as well as for developing future treatments.

Pathological cardiac hypertrophy occurs in response to numerous increased afterload stimuli and precedes irreversible heart failure (HF). Therefore, therapies that ameliorate pathological cardiac hypertrophy are urgently required. Sirtuin 3 (Sirt3) is a main member of histone deacetylase class III and is a crucial anti-oxidative stress agent. Therapeutically enhancing the Sirt3 transfection efficiency in the heart would broaden the potential clinical application of Sirt3. Ultrasound-targeted microbubble destruction (UTMD) is a prospective, noninvasive, repeatable, and targeted gene delivery technique. In the present study, we explored the potential and safety of UTMD as a delivery tool for Sirt3 in hypertrophic heart tissues using adult male Bama miniature pigs. Pigs were subjected to ear vein delivery of human Sirt3 together with UTMD of cationic microbubbles (CMBs). Fluorescence imaging, western blotting, and quantitative real -time PCR revealed that the targeted destruction of ultrasonic CMBs in cardiac tissues greatly boosted Sirt3 delivery. Overexpression of Sirt3 ameliorated oxidative stress and partially improved the diastolic function and prevented the apoptosis and profibrotic response. Lastly, our data revealed that Sirt3 may regulate the potential transcription of catalase and MnSOD through Foxo3a. Combining the advantages of ultrasound CMBs with preclinical hypertrophy large animal models for gene delivery, we established a classical hypertrophy model as well as a strategy for the targeted delivery of genes to hypertrophic heart tissues. Since oxidative stress, fibrosis and apoptosis are indispensable in the evolution of cardiac hypertrophy and heart failure, our findings suggest that Sirt3 is a promising therapeutic option for these diseases.Statement of SignificancePathological cardiac hypertrophy is a central prepathology of heart failure and is seen to eventually pre-cede it. Feasible targets that may prevent or reverse disease progression are scarce and urgently needed. In this study, we developed surface-filled lipid octafluoropropane gas core cationic microbubbles that could target the release of human Sirt3 reactivating the endogenous Sirt3 in hypertrophic hearts and protect against oxidative stress in a pig model of cardiac hypertrophy induced by aortic banding. Sirt3-CMBs may enhance cardiac diastolic function and ameliorate fibrosis and apoptosis. Our work provides a classical cationic lipid-based, UTMD-mediated Sirt3 delivery system for the treatment of Sirt3 in patients with established cardiac hypertrophy, as well as a promising therapeutic target to combat pathological cardiac hypertrophy.(c) 2023 The Author(s). Published by Elsevier Ltd on behalf of Acta Materialia Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

BACKGROUND:Compared with bone marrow mesenchymal stem cells (BMSCs), decidual mesenchymal stem cells (DMSCs) are easy to obtain and exhibit excellent angiogenic effects, but their role in cell transplantation after myocardial infarction (MI) remains unclear.METHODS:BMSCs and DMSCs were harvested from healthy donors. The effects of both cell types on angiogenesis were observed in vitro. Metabonomics analysis was performed to compare different metabolites and screen critical metabolic pathways. A murine model of acute myocardial infarction (AMI) was established, which was randomized into five groups (control, BMSC, DMSC, DMSC + ODCshRNA and BMSC + ODC consisting of 50 animals, equally divided into each group). The therapeutic effect of DMSCs on MI in rats was assessed based on neovascularization and cardiac remodeling.RESULTS:DMSCs exhibited a better angiogenic effect on human umbilical vein endothelial cells (HUVECs) than BMSCs in vitro. In addition, ornithine metabolism, which is associated with vascularization, was significantly increased in DMSCs. The transplantation of DMSCs in the rat MI model significantly enhanced angiogenesis of the infarct border area and improved cardiac remodeling and dysfunction postinfarction compared with BMSCs. Furthermore, inhibition of ornithine metabolism by silencing ornithine decarboxylase (ODC) in DMSCs partly abolished the benefits of DMSC transplantation.CONCLUSION:Compared with BMSCs, DMSCs exhibited better efficacy in improving revascularization and heart remodeling post-MI via the activation of ODC-associated ornithine metabolism.