Journal of molecular and cellular cardiology最新文献

{"title":"Myocardial glycophagy flux dysregulation and glycogen accumulation characterize diabetic cardiomyopathy","authors":"Kimberley M. Mellor ,&nbsp;Upasna Varma ,&nbsp;Parisa Koutsifeli ,&nbsp;Lorna J. Daniels ,&nbsp;Victoria L. Benson ,&nbsp;Marco Annandale ,&nbsp;Xun Li ,&nbsp;Yohanes Nursalim ,&nbsp;Johannes V. Janssens ,&nbsp;Kate L. Weeks ,&nbsp;Kim L. Powell ,&nbsp;Terence J. O'Brien ,&nbsp;Rajesh Katare ,&nbsp;Rebecca H. Ritchie ,&nbsp;James R. Bell ,&nbsp;Roberta A. Gottlieb ,&nbsp;Lea M.D. Delbridge","doi":"10.1016/j.yjmcc.2024.02.009","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2024.02.009","url":null,"abstract":"<div><p>Diabetic heart disease morbidity and mortality is escalating. No specific therapeutics exist and mechanistic understanding of diabetic cardiomyopathy etiology is lacking. While lipid accumulation is a recognized cardiomyocyte phenotype of diabetes, less is known about glycolytic fuel handling and storage. Based on in vitro studies, we postulated the operation of an autophagy pathway in the myocardium specific for glycogen homeostasis – glycophagy. Here we visualize occurrence of cardiac glycophagy and show that the diabetic myocardium is characterized by marked glycogen elevation and altered cardiomyocyte glycogen localization. We establish that cardiac glycophagy flux is disturbed in diabetes. Glycophagy may represent a potential therapeutic target for alleviating the myocardial impacts of metabolic disruption in diabetic heart disease.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824000348/pdfft?md5=51d153eaf3e8c191b20f9b2d30c11d2b&pid=1-s2.0-S0022282824000348-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140121884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translating myosin-binding protein C and titin abnormalities to whole-heart function using a novel calcium-contraction coupling model","authors":"Theo Arts ,&nbsp;Aurore Lyon ,&nbsp;Tammo Delhaas ,&nbsp;Diederik W.D. Kuster ,&nbsp;Jolanda van der Velden ,&nbsp;Joost Lumens","doi":"10.1016/j.yjmcc.2024.03.001","DOIUrl":"10.1016/j.yjmcc.2024.03.001","url":null,"abstract":"<div><p>Mutations in cardiac myosin-binding protein C (cMyBP-C) or titin may respectively lead to hypertrophic (HCM) or dilated (DCM) cardiomyopathies. The mechanisms leading to these phenotypes remain unclear because of the challenge of translating cellular abnormalities to whole-heart and system function.</p><p>We developed and validated a novel computer model of calcium-contraction coupling incorporating the role of cMyBP-C and titin based on the key assumptions: 1) tension in the thick filament promotes cross-bridge attachment mechanochemically, 2) with increasing titin tension, more myosin heads are unlocked for attachment, and 3) cMyBP-C suppresses cross-bridge attachment.</p><p>Simulated stationary calcium-tension curves, isotonic and isometric contractions, and quick release agreed with experimental data. The model predicted that a loss of cMyBP-C function decreases the steepness of the calcium-tension curve, and that more compliant titin decreases the level of passive and active tension and its dependency on sarcomere length. Integrating this cellular model in the CircAdapt model of the human heart and circulation showed that a loss of cMyBP-C function resulted in HCM-like hemodynamics with higher left ventricular end-diastolic pressures and smaller volumes. More compliant titin led to higher diastolic pressures and ventricular dilation, suggesting DCM-like hemodynamics.</p><p>The novel model of calcium-contraction coupling incorporates the role of cMyBP-C and titin. Its coupling to whole-heart mechanics translates changes in cellular calcium-contraction coupling to changes in cardiac pump and circulatory function and identifies potential mechanisms by which cMyBP-C and titin abnormalities may develop into HCM and DCM phenotypes. This modeling platform may help identify distinct mechanisms underlying clinical phenotypes in cardiac diseases.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S002228282400035X/pdfft?md5=af5e6d78ea26d1f24fac0a4fc96bb8ab&pid=1-s2.0-S002228282400035X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140094229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling ionizing radiation-induced cardiovascular dysfunction with human iPSC-derived engineered heart tissues","authors":"Xu Cao ,&nbsp;Dilip Thomas ,&nbsp;Luke A. Whitcomb ,&nbsp;Mingqiang Wang ,&nbsp;Anushree Chatterjee ,&nbsp;Adam J. Chicco ,&nbsp;Michael M. Weil ,&nbsp;Joseph C. Wu","doi":"10.1016/j.yjmcc.2023.11.012","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2023.11.012","url":null,"abstract":"","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140000416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular nucleic acid binding protein facilitates cardiac repair after myocardial infarction by activating β-catenin signaling","authors":"Chong Du ,&nbsp;Shan Zhao ,&nbsp;Tiankai Shan ,&nbsp;Xudong Han ,&nbsp;Qiqi Jiang ,&nbsp;Jiawen Chen ,&nbsp;Lingfeng Gu ,&nbsp;Tianwen Wei ,&nbsp;Tongtong Yang ,&nbsp;Sibo Wang ,&nbsp;Hao Wang ,&nbsp;Xuejiang Guo ,&nbsp;Liansheng Wang","doi":"10.1016/j.yjmcc.2024.02.008","DOIUrl":"10.1016/j.yjmcc.2024.02.008","url":null,"abstract":"<div><p>The regenerative capacity of the adult mammalian heart is limited, while the neonatal heart is an organ with regenerative and proliferative ability. Activating adult cardiomyocytes (CMs) to re-enter the cell cycle is an effective therapeutic method for ischemic heart disease such as myocardial infarction (MI) and heart failure. Here, we aimed to reveal the role and potential mechanisms of cellular nucleic acid binding protein (CNBP) in cardiac regeneration and repair after heart injury. CNBP is highly expressed within 7 days post-birth while decreases significantly with the loss of regenerative ability. <em>In vitro</em>, overexpression of CNBP promoted CM proliferation and survival, whereas knockdown of CNBP inhibited these processes. <em>In vivo</em>, knockdown of CNBP in CMs robustly hindered myocardial regeneration after apical resection in neonatal mice. In adult MI mice, CM-specific CNBP overexpression in the infarct border zone ameliorated myocardial injury in acute stage and facilitated CM proliferation and functional recovery in the long term. Quantitative proteomic analysis with TMT labeling showed that CNBP overexpression promoted the DNA replication, cell cycle progression, and cell division. Mechanically, CNBP overexpression increased the expression of β-catenin and its downstream target genes CCND1 and c-myc; Furthermore, Luciferase reporter and Chromatin immunoprecipitation (ChIP) assays showed that CNBP could directly bind to the β-catenin promoter and promote its transcription. CNBP also upregulated the expression of G1/S-related cell cycle genes CCNE1, CDK2, and CDK4. Collectively, our study reveals the positive role of CNBP in promoting cardiac repair after injury, providing a new therapeutic option for the treatment of MI.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140022006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATF6 protects against protein misfolding during cardiac hypertrophy","authors":"Christoph Hofmann ,&nbsp;Marjan Aghajani ,&nbsp;Cecily D. Alcock ,&nbsp;Erik A. Blackwood ,&nbsp;Clara Sandmann ,&nbsp;Nicole Herzog ,&nbsp;Julia Groß ,&nbsp;Lars Plate ,&nbsp;R. Luke Wiseman ,&nbsp;Randal J. Kaufman ,&nbsp;Hugo A. Katus ,&nbsp;Tobias Jakobi ,&nbsp;Mirko Völkers ,&nbsp;Christopher C. Glembotski ,&nbsp;Shirin Doroudgar","doi":"10.1016/j.yjmcc.2024.02.001","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2024.02.001","url":null,"abstract":"<div><p>Cardiomyocytes activate the unfolded protein response (UPR) transcription factor ATF6 during pressure overload-induced hypertrophic growth. The UPR is thought to increase ER protein folding capacity and maintain proteostasis. ATF6 deficiency during pressure overload leads to heart failure, suggesting that ATF6 protects against myocardial dysfunction by preventing protein misfolding. However, conclusive evidence that ATF6 prevents toxic protein misfolding during cardiac hypertrophy is still pending. Here, we found that activation of the UPR, including ATF6, is a common response to pathological cardiac hypertrophy in mice. ATF6 KO mice failed to induce sufficient levels of UPR target genes in response to chronic isoproterenol infusion or transverse aortic constriction (TAC), resulting in impaired cardiac growth. To investigate the effects of ATF6 on protein folding, the accumulation of poly-ubiquitinated proteins as well as soluble amyloid oligomers were directly quantified in hypertrophied hearts of WT and ATF6 KO mice. Whereas only low levels of protein misfolding was observed in WT hearts after TAC, ATF6 KO mice accumulated increased quantities of misfolded protein, which was associated with impaired myocardial function. Collectively, the data suggest that ATF6 plays a critical adaptive role during cardiac hypertrophy by protecting against protein misfolding.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139937020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophils are indispensable for adverse cardiac remodeling in heart failure","authors":"Sergey Antipenko ,&nbsp;Nicolas Mayfield ,&nbsp;Miki Jinno ,&nbsp;Matthias Gunzer ,&nbsp;Mohamed Ameen Ismahil ,&nbsp;Tariq Hamid ,&nbsp;Sumanth D. Prabhu ,&nbsp;Gregg Rokosh","doi":"10.1016/j.yjmcc.2024.02.005","DOIUrl":"10.1016/j.yjmcc.2024.02.005","url":null,"abstract":"<div><p>Persistent immune activation contributes significantly to left ventricular (LV) dysfunction and adverse remodeling in heart failure (HF). In contrast to their well-known essential role in acute myocardial infarction (MI) as first responders that clear dead cells and facilitate subsequent reparative macrophage polarization, the role of neutrophils in the pathobiology of chronic ischemic HF is poorly defined. To determine the importance of neutrophils in the progression of ischemic cardiomyopathy, we measured their production, levels, and activation in a mouse model of chronic HF 8 weeks after permanent coronary artery ligation and large MI. In HF mice, neutrophils were more abundant both locally in failing myocardium (more in the border zone) and systemically in the blood, spleen, and bone marrow, together with increased BM granulopoiesis. There were heightened stimuli for neutrophil recruitment and trafficking in HF, with increased myocardial expression of the neutrophil chemoattract chemokines CXCL1 and CXCL5, and increased neutrophil chemotactic factors in the circulation. HF neutrophil NETotic activity was increased in vitro with coordinate increases in circulating neutrophil extracellular traps (NETs) in vivo. Neutrophil depletion with either antibody-based or genetic approaches abrogated the progression of LV remodeling and fibrosis at both intermediate and late stages of HF. Moreover, analogous to murine HF, the plasma milieu in human acute decompensated HF strongly promoted neutrophil trafficking. Collectively, these results support a key tissue-injurious role for neutrophils and their associated cytotoxic products in ischemic cardiomyopathy and suggest that neutrophils are potential targets for therapeutic immunomodulation in this disease.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824000221/pdfft?md5=7ff0ec432d0ddb4042171545b30beace&pid=1-s2.0-S0022282824000221-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139931541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbial metabolite trimethylamine N-oxide induces aortic dissection","authors":"Shan Huang ,&nbsp;Shijuan Gao ,&nbsp;Yihui Shao ,&nbsp;Ping Li ,&nbsp;Jie Lu ,&nbsp;Ke Xu ,&nbsp;Zeyi Zhou ,&nbsp;Yulin Li ,&nbsp;Jie Du","doi":"10.1016/j.yjmcc.2024.02.007","DOIUrl":"10.1016/j.yjmcc.2024.02.007","url":null,"abstract":"<div><p>Aortic dissection (AD) is the most catastrophic vascular disease with a high mortality rate. Trimethylamine N-oxide (TMAO), a gut microbial metabolite, has been implicated in the pathogenesis of cardiovascular diseases. However, the role of TMAO in AD and the underlying mechanisms remain unclear. This study aimed to explore the effects of TMAO on AD. Plasma and fecal samples from patients with AD and healthy individuals were collected to analyze TMAO levels and gut microbial species, respectively. The plasma levels of TMAO were significantly higher in 253 AD patients compared with those in 98 healthy subjects (3.47, interquartile range (IQR): 2.33 to 5.18 μM <em>vs.</em> 1.85, IQR: 1.40 to 3.35 μM; <em>p</em> &lt; 0.001). High plasma TMAO levels were positively associated with AD severity. An increase in the relative abundance of TMA-producing genera in patients with AD was revealed using 16S rRNA sequencing. In the angiotensin II or β-aminopropionitrile-induced rodent model of AD, mice fed a TMAO-supplemented diet were more likely to develop AD compared to mice fed a normal diet. Conversely, TMAO depletion mitigated AD formation in the BAPN model. RNA sequencing of aortic endothelial cells isolated from mice administered TMAO revealed significant upregulation of genes involved in inflammatory pathways. The <em>in vitro</em> experiments verified that TMAO promotes endothelial dysfunction and activates nuclear factor (NF)-κB signaling. The <em>in vivo</em> BAPN-induced AD model confirmed that TMAO increased aortic inflammation. Our study demonstrates that the gut microbial metabolite TMAO aggravates the development of AD at least in part by inducing endothelial dysfunction and inflammation. This study provides new insights into the etiology of AD and ideas for its management.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139921583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel roles of cardiac-derived erythropoietin in cardiac development and function","authors":"Melissa A. Allwood ,&nbsp;Brittany A. Edgett ,&nbsp;Mathew J. Platt ,&nbsp;Jade P. Marrow ,&nbsp;Bridget Coyle-Asbil ,&nbsp;Emma J.B. Holjak ,&nbsp;Victoria L. Nelson ,&nbsp;Swara Bangali ,&nbsp;Razan Alshamali ,&nbsp;Kathy Jacyniak ,&nbsp;Jorden M. Klein ,&nbsp;Laura Farquharson ,&nbsp;Nadya Romanova ,&nbsp;Victoria Northrup ,&nbsp;Leslie M. Ogilvie ,&nbsp;Anmar Ayoub ,&nbsp;Kjetil Ask ,&nbsp;Matthew K. Vickaryous ,&nbsp;Gregory M.T. Hare ,&nbsp;Keith R. Brunt ,&nbsp;Jeremy A. Simpson","doi":"10.1016/j.yjmcc.2024.01.006","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2024.01.006","url":null,"abstract":"<div><p>The role of erythropoietin (EPO) has extended beyond hematopoiesis to include cytoprotection, inotropy, and neurogenesis. Extra-renal EPO has been reported for multiple tissue/cell types, but the physiological relevance remains unknown. Although the EPO receptor is expressed by multiple cardiac cell types and human recombinant EPO increases contractility and confers cytoprotection against injury, whether the heart produces physiologically meaningful amounts of EPO in vivo is unclear. We show a distinct circadian rhythm of cardiac EPO mRNA expression in adult mice and increased mRNA expression during embryogenesis, suggesting physiological relevance to cardiac EPO production throughout life. We then generated constitutive, cardiomyocyte-specific EPO knockout mice driven by the Mlc2v promoter (EPOfl/fl:Mlc2v-cre+/−; EPO^Δ/Δ-CM). During cardiogenesis, cardiac EPO mRNA expression and cellular proliferation were reduced in EPO^Δ/Δ-CM hearts. However, in adult EPO^{Δ/Δ- CM} mice, total heart weight was preserved through increased cardiomyocyte cross-sectional area, indicating the reduced cellular proliferation was compensated for by cellular hypertrophy. Echocardiography revealed no changes in cardiac dimensions, with modest reductions in ejection fraction, stroke volume, and tachycardia, whereas invasive hemodynamics showed increased cardiac contractility and lusitropy. Paradoxically, EPO mRNA expression in the heart was elevated in adult EPO^Δ/Δ-CM, along with increased serum EPO protein content and hematocrit. Using RNA fluorescent in situ hybridization, we found that Epo RNA colocalized with endothelial cells in the hearts of adult EPO^Δ/Δ-CM mice, identifying the endothelial cells as a cell responsible for the EPO hyper-expression. Collectively, these data identify the first physiological roles for cardiomyocyte-derived EPO. We have established cardiac EPO mRNA expression is a complex interplay of multiple cell types, where loss of embryonic cardiomyocyte EPO production results in hyper-expression from other cells within the adult heart.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139908178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabidiol protects against acute aortic dissection by inhibiting macrophage infiltration and PMAIP1-induced vascular smooth muscle cell apoptosis","authors":"Yilong Guo ,&nbsp;Yang Che ,&nbsp;Xuelin Zhang ,&nbsp;Zongna Ren ,&nbsp;Yinan Chen ,&nbsp;Liliang Guo ,&nbsp;Lin Mao ,&nbsp;Ren Wei ,&nbsp;Xiang Gao ,&nbsp;Tao Zhang ,&nbsp;Li Wang ,&nbsp;Wei Guo","doi":"10.1016/j.yjmcc.2024.02.006","DOIUrl":"10.1016/j.yjmcc.2024.02.006","url":null,"abstract":"<div><p>Acute aortic dissection (AAD) progresses rapidly and is associated with high mortality; therefore, there remains an urgent need for pharmacological agents that can protect against AAD. Herein, we examined the therapeutic effects of cannabidiol (CBD) in AAD by establishing a suitable mouse model. In addition, we performed human AAD single-cell RNA sequencing and mouse AAD bulk RNA sequencing to elucidate the potential underlying mechanism of CBD. Pathological assays and <em>in vitro</em> studies were performed to verify the results of the bioinformatic analysis and explore the pharmacological function of CBD. In a β-aminopropionitrile (BAPN)-induced AAD mouse model, CBD reduced AAD-associated morbidity and mortality, alleviated abnormal enlargement of the ascending aorta and aortic arch, and suppressed macrophage infiltration and vascular smooth muscle cell (VSMC) apoptosis. Bioinformatic analysis revealed that the pro-apoptotic gene <em>PMAIP1</em> was highly expressed in human and mouse AAD samples, and CBD could inhibit <em>Pmaip1</em> expression in AAD mice. Using human aortic VSMCs (HAVSMCs) co-cultured with M1 macrophages, we revealed that CBD alleviated HAVSMCs mitochondrial-dependent apoptosis by suppressing the BAPN-induced overexpression of <em>PMAIP1</em> in M1 macrophages. PMAIP1 potentially mediates HAVSMCs apoptosis by regulating Bax and Bcl2 expression. Accordingly, CBD reduced AAD-associated morbidity and mortality and mitigated the progression of AAD in a mouse model. The CBD-induced effects were potentially mediated by suppressing macrophage infiltration and PMAIP1 (primarily expressed in macrophages)-induced VSMC apoptosis. Our findings offer novel insights into M1 macrophages and HAVSMCs interaction during AAD progression, highlighting the potential of CBD as a therapeutic candidate for AAD treatment.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824000233/pdfft?md5=873d8aef4c1c93c769c7f71ed255472d&pid=1-s2.0-S0022282824000233-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139921610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NCoR1 limits angiogenic capacity by altering Notch signaling","authors":"Tom Teichmann ,&nbsp;Pedro Malacarne ,&nbsp;Simonida Zehr ,&nbsp;Stefan Günther ,&nbsp;Beatrice Pflüger-Müller ,&nbsp;Timothy Warwick ,&nbsp;Ralf P. Brandes","doi":"10.1016/j.yjmcc.2024.02.003","DOIUrl":"https://doi.org/10.1016/j.yjmcc.2024.02.003","url":null,"abstract":"<div><p>Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), silencing mediator of retinoid and thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including <em>ESM1</em>, <em>DLL4</em> and <em>NOTCH4</em>, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of <em>NCOR1</em> promotes RBPJk activity. Furthermore, NCoR1 depletion prompts upregulation of several elements in the Notch signaling cascade. Downregulation of <em>NOTCH4</em>, but not <em>NOTCH1</em>, prevented the positive effect of <em>NCOR1</em> knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing <em>NCOR1</em> expression is an attractive approach to promote angiogenic function.</p></div>","PeriodicalId":16402,"journal":{"name":"Journal of molecular and cellular cardiology","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0022282824000208/pdfft?md5=9db7d592b52f1dcd24dff70f208e8c7a&pid=1-s2.0-S0022282824000208-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139737674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}