Cardiovascular Research最新文献

{"title":"A hidden role of Th17 cells in doxorubicin-induced cardiac ferroptosis.","authors":"Yangfeng Hou, Wentao Gao, Kathy O Lui","doi":"10.1093/cvr/cvae226","DOIUrl":"10.1093/cvr/cvae226","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1989-1991"},"PeriodicalIF":10.2,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblast-specific TGF-β signaling mediates cardiac dysfunction, fibrosis, and hypertrophy in obese diabetic mice.","authors":"Izabela Tuleta, Anis Hanna, Claudio Humeres, Jennifer T Aguilan, Simone Sidoli, Fenglan Zhu, Nikolaos G Frangogiannis","doi":"10.1093/cvr/cvae210","DOIUrl":"10.1093/cvr/cvae210","url":null,"abstract":"<p><strong>Aims: </strong>Transforming growth factor (TGF)-β is up-regulated in the diabetic myocardium and may mediate fibroblast activation. We aimed at examining the role of TGF-β-induced fibroblast activation in the pathogenesis of diabetic cardiomyopathy.</p><p><strong>Methods and results: </strong>We generated lean and obese db/db mice with fibroblast-specific loss of TbR2, the Type 2 receptor-mediating signaling through all three TGF-β isoforms, and mice with fibroblast-specific Smad3 disruption. Systolic and diastolic function, myocardial fibrosis, and hypertrophy were assessed. Transcriptomic studies and in vitro experiments were used to dissect mechanisms of fibroblast activation. Fibroblast-specific TbR2 loss attenuated systolic and diastolic dysfunction in db/db mice. The protective effects of fibroblast TbR2 loss in db/db mice were associated with attenuated fibrosis and reduced cardiomyocyte hypertrophy, suggesting that in addition to their role in fibrous tissue deposition, TGF-β-stimulated fibroblasts may also exert paracrine actions on cardiomyocytes. Fibroblast-specific Smad3 loss phenocopied the protective effects of fibroblast TbR2 loss in db/db mice. Db/db fibroblasts had increased expression of genes associated with oxidative response (such as Fmo2, encoding flavin-containing monooxygenase 2), matricellular genes (such as Thbs4 and Fbln2), and Lox (encoding lysyl oxidase). Ingenuity pathway analysis (IPA) predicted that neurohumoral mediators, cytokines, and growth factors (such as AGT, TGFB1, and TNF) may serve as important upstream regulators of the transcriptomic profile of diabetic mouse fibroblasts. IPA of scRNA-seq data identified TGFB1, p53, MYC, PDGF-BB, EGFR, and WNT3A/CTNNB1 as important upstream regulators underlying fibroblast activation in db/db hearts. Comparison of the transcriptome of fibroblasts from db/db mice with fibroblast-specific Smad3 loss and db/db Smad3 fl/fl controls identified Thbs4 [encoding thrombospondin-4 (TSP-4), a marker of activated fibroblasts] as a candidate diabetes-induced fibrogenic mediator. However, in vitro experiments showed no significant activating effects of matricellular or intracellular TSP-4 on cardiac fibroblasts.</p><p><strong>Conclusion: </strong>Fibroblast-specific TGF-β/Smad3 signaling mediates ventricular fibrosis, hypertrophy, and dysfunction in Type 2 diabetes.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2047-2063"},"PeriodicalIF":10.2,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma biomarkers of inflammation associate with blood pressure and arterial stiffness in adolescents after very preterm birth.","authors":"Anja Meissner, Jonas Liefke, Frank Matthes, Eva Morsing, David Ley, Erik Hedström","doi":"10.1093/cvr/cvae192","DOIUrl":"10.1093/cvr/cvae192","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1992-1995"},"PeriodicalIF":10.2,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin receptors in vascular smooth muscle cells regulate plaque stability of atherosclerosis.","authors":"Qian Li, Jialin Fu, Kyoungmin Park, Hetal Shah, Qin Li, I Hsien Wu, George L King","doi":"10.1093/cvr/cvae193","DOIUrl":"10.1093/cvr/cvae193","url":null,"abstract":"<p><strong>Aims: </strong>Increased prevalence of acute myocardial infarction related to diabetes and insulin resistance is associated with an elevated risk of unstable atherosclerotic plaques, which are characterized by reduced vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) and increased inflammation. Thus, insulin resistance may reduce plaque stability, as deleting insulin receptors (IRs) in VSMCs decreases their proliferation and enhances apoptosis.</p><p><strong>Methods and results: </strong>Direct effects of insulin on VSMCs to alter plaque composition were studied using mice with double knockout of ApoE and IR genes in VSMCs with SMIRKO/ApoE-/-, Myh11-CreERT2EYFP+/ApoE-/-, and Myh11-CreERT2EYFP+IRKO/ApoE-/- mice, which were also used for lineage tracing studies. Compared with ApoE-/- mice, SMIRKO/ApoE-/- mice exhibited more atherosclerotic plaques, which contained less VSMCs and collagen but increased levels of VSMC apoptosis and necrotic areas. Lineage tracing studies showed that Icam1+ Vcam1+ VSMC was inflammatory, which increased in the aortas of Myh11-CreERT2EYFP+IRKO/ApoE-/- mice compared with control mice. Isolated VSMCs lacking IRs expressed higher inflammatory cytokines than cells with IRs. Cell-based studies indicated that insulin's anti-apoptotic and pro-proliferative effects in VSMCs were mediated via activation of the IR/Akt pathway, which were decreased in VSMCs from SMIRKO or high-fat diet mice. An analysis of the IR targets that regulated inflammatory cytokines in VSMCs showed that thrombospondin 1 (Thbs1) and Mmp2 were consistently increased with a loss of IRs. Insulin inhibited Thbs1 expression, but not Mmp2 expression, through p-Akt/p-FoxO1 pathways in VSMCs from ApoE-/- mice, and was impaired in cells from SMIRKO/ApoE-/- mice. Thbs1 further induced Icam1 and Mmp2 expressions in VSMCs.</p><p><strong>Conclusion: </strong>Insulin via IRs has significant actions in VSMCs to decrease inflammation, apoptosis, and ECM turnover via the activation of Akt and FoxO1 pathways. The inhibition of insulin actions and related pathways related to insulin resistance and diabetes may contribute to the formation of unstable atherosclerotic plaques.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2017-2030"},"PeriodicalIF":10.2,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA binding protein with multiple splicing (RBPMS) promotes contractile phenotype splicing in human embryonic stem cell-derived vascular smooth muscle cells.","authors":"Aishwarya G Jacob, Ilias Moutsopoulos, Alex Petchey, Rafael Kollyfas, Vincent R Knight-Schrijver, Irina Mohorianu, Sanjay Sinha, Christopher W J Smith","doi":"10.1093/cvr/cvae198","DOIUrl":"10.1093/cvr/cvae198","url":null,"abstract":"<p><strong>Aims: </strong>Differentiated vascular smooth muscle cells (VSMCs) express a unique network of mRNA isoforms via smooth muscle-specific alternative pre-mRNA splicing (SM-AS) in functionally critical genes, including those comprising the contractile machinery. We previously described RNA Binding Protein with Multiple Splicing (RBPMS) as a potent driver of differentiated SM-AS in the rat PAC1 VSMC cell line. What is unknown is how RBPMS affects VSMC phenotype and behaviour. Here, we aimed to dissect the role of RBPMS in SM-AS in human cells and determine the impact on VSMC phenotypic properties.</p><p><strong>Methods and results: </strong>We used human embryonic stem cell-derived VSMCs (hESC-VSMCs) as our platform. hESC-VSMCs are inherently immature, and we found that they display only partially differentiated SM-AS patterns while RBPMS protein levels are low. We found that RBPMS over-expression induces SM-AS patterns in hESC-VSMCs akin to the contractile tissue VSMC splicing patterns. We present in silico and experimental findings that support RBPMS' splicing activity as mediated through direct binding and via functional cooperativity with splicing factor RBFOX2 on a significant subset of targets. We also demonstrate that RBPMS can alter the motility and the proliferative properties of hESC-VSMCs to mimic a more differentiated state.</p><p><strong>Conclusion: </strong>Overall, this study emphasizes a critical role for RBPMS in establishing the contractile phenotype splicing programme of human VSMCs.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2104-2116"},"PeriodicalIF":10.2,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11646123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early coronary revascularization among 'stable' patients with non-ST-segment elevation acute coronary syndromes: the role of diabetes and age.","authors":"Natalia Fabin, Edina Cenko, Maria Bergami, Jinsung Yoon, Giuseppe Vadalà, Guiomar Mendieta, Sasko Kedev, Jorgo Kostov, Marija Vavlukis, Elif Vraynko, Davor Miličić, Zorana Vasiljevic, Marija Zdravkovic, Lina Badimon, Alfredo R Galassi, Olivia Manfrini, Raffaele Bugiardini","doi":"10.1093/cvr/cvae190","DOIUrl":"10.1093/cvr/cvae190","url":null,"abstract":"<p><strong>Aims: </strong>To investigate the impact of an early coronary revascularization (<24 h) compared with initial conservative strategy on clinical outcomes in diabetic patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) who are in stable condition at hospital admission.</p><p><strong>Methods and results: </strong>The International Survey of Acute Coronary Syndromes database was queried for a sample of diabetic and nondiabetic patients with diagnosis of NSTE-ACS. Patients with cardiac arrest, haemodynamic instability, and serious ventricular arrhythmias were excluded. The characteristics between groups were adjusted using logistic regression and inverse probability of treatment weighting models. Primary outcome measure was all-cause 30-day mortality. Risk ratios (RRs) and odds ratios (ORs) with their 95% confidence intervals (CIs) were employed. Of the 7589 NSTE-ACS patients identified, 2343 were diabetics. The data show a notable reduction in mortality for the elderly (>65 years) undergoing early revascularization compared to those receiving an initial conservative strategy both in the diabetic (3.3% vs. 6.7%; RR: 0.48; 95% CI: 0.28-0.80) and nondiabetic patients (2.7% vs. 4.7%: RR: 0.57; 95% CI: 0.36-0.90). In multivariate analyses, diabetes was a strong independent predictor of mortality in the elderly (OR: 1.43; 95% CI: 1.03-1.99), but not in the younger patients (OR: 1.04; 95% CI: 0.53-2.06).</p><p><strong>Conclusion: </strong>Early coronary revascularization does not lead to any survival advantage within 30 days from admission in young NSTE-ACS patients who present to hospital in stable conditions with and without diabetes. An early invasive management strategy may be best reserved for the elderly. Factors beyond revascularization are of considerable importance for outcome in elderly diabetic subjects with NSTE-ACS.</p><p><strong>Clinical trial number: </strong>ClinicalTrials.gov: NCT01218776.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"2064-2077"},"PeriodicalIF":10.2,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142086005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardioprotective effect of 19,20-epoxydocosapentaenoic acid (19,20-EDP) in ischemic injury involves direct activation of mitochondrial sirtuin 3","authors":"Ahmed M Darwesh, Liye Fang, Tariq R Altamimi, K Lockhart Jamieson, Wesam Bassiouni, Robert Valencia, Andy Huang, Faqi Wang, Hao Zhang, Marawan Ahmed, Keshav Gopal, Yongneng Zhang, Evangelos D Michelakis, John R Ussher, Matthew L Edin, Darryl C Zeldin, Khaled Barakat, Gavin Y Oudit, Zamaneh Kassiri, Gary D Lopaschuk, John M Seubert","doi":"10.1093/cvr/cvae252","DOIUrl":"https://doi.org/10.1093/cvr/cvae252","url":null,"abstract":"Aims Although current clinical therapies following myocardial infarction have improved patient outcomes, morbidity, and mortality rates secondary to ischemic and ischemia reperfusion (IR) injury remains high. Maintaining mitochondrial quality is essential to limit myocardial damage following cardiac ischemia and IR injury. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in regulating mitochondrial function and cardiac energy metabolism. In the current study, we hypothesize that 19,20-epoxydocosapentaenoic acid (19,20-EDP) attenuates cardiac IR injury via stimulating mitochondrial SIRT3. Methods and Results Ex vivo models of isolated heart perfusions were performed in C57BL/6 mice to assess the effect of 19,20-EDP on cardiac function and energy metabolism following IR injury. In vivo permanent occlusion of the left anterior descending coronary artery (LAD) was performed to induce myocardial infarction (MI), mice were administered 19,20-EDP with or without the SIRT3 selective inhibitor 3-TYP. Mitochondrial SIRT3 targets and respiration were assessed in human left ventricular (LV) tissues obtained from individuals with ischemic heart disease (IHD) and compared to non-failing controls (NFC). Binding affinity of 19,20-EDP to human SIRT3 was assessed using molecular modeling and fluorescence thermal shift assay. Results demonstrated hearts treated with 19,20-EDP had improved post-ischemic cardiac function, better glucose oxidation rates and enhanced cardiac efficiency. The cardioprotective effects were associated with enhanced mitochondrial SIRT3 activity. Interestingly, treatment with 19,20-EDP markedly improved mitochondrial respiration and SIRT3 activity in human left ventricle (LV) fibers with IHD compared to NFC. Moreover, 19,20-EDP was found to bind to the human SIRT3 protein enhancing the NAD+ -complex stabilization leading to improved SIRT3 activity. Importantly, the beneficial effects of 19,20-EDP were abolished by SIRT3 inhibition or using the S149A mutant SIRT3. Conclusion These data demonstrate that 19,20-EDP-mediated cardioprotective mechanisms against ischemia and IR injury involve mitochondrial SIRT3, resulting in improved cardiac efficiency.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"67 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The m6A demethylase ALKBH5 is a novel epigenetic regulator of aortic valve calcification","authors":"Yueheng Wang, Shengping He, Lan Lan, Hongjiao Yu, Huan Zhao, Yuchen Xie, Guoli Zhong, Liang Yuan, Kun Li, Xiao Hu, Vicky E Macrae, Xiaodong Fu, Guojun Chen, Dongxing Zhu","doi":"10.1093/cvr/cvae253","DOIUrl":"https://doi.org/10.1093/cvr/cvae253","url":null,"abstract":"Aims Calcific aortic valve disease (CAVD) is a common heart valve disease with significant clinical consequences. The mechanisms that drive the pathogenesis of CAVD remain to be fully elucidated. N6-methyladenosine (m6A), the most prevalent RNA epigenetic regulator, has recently been implicated in cardiovascular disease, but its role in CAVD has yet to be investigated. In this study, we investigated the potential function of m6A modification in CAVD. Methods and Results Using clinical samples from CAVD patients in combination with human valve interstitial cell (hVIC) calcification model, we screened the expression of m6A modulators and discovered that ALKBH5 alkB homolog 5, RNA demethylase (ALKBH5), a key m6A demethylase, was significantly down-regulated in calcified hVICs and human aortic valves. Consistently, increased m6A levels were seen in calcified hVICs, and treated with 3-deazaadenosine (DAA), an inhibitor of m6A modification, significantly reduced hVIC osteogenic differentiation and calcification. In addition, we showed that silencing of ALKBH5 expression increased global m6A levels, and accelerated hVIC osteogenic differentiation and calcification, whereas overexpression of ALKBH5 resulted in the opposite effect. We demonstrated that ALKBH5 directly modulate m6A levels of TGFBR2 and its mRNA stability, leading to altered TGFBR2 expression and SMAD2 signaling in hVICs. We further showed that inhibition of TGFBR2 or knockdown of SMAD2 attenuated ALKBH5 knockdown-induced hVIC osteogenic differentiation and calcification. The expression of the m6A reader protein YTH N6-methyladenosine RNA binding protein F1 (YTHDF1) was upregulated during the process of hVIC calcification. Intriguingly, we revealed that the ALKBH5 silencing-induced increased hVIC osteogenic differentiation and calcification were abolished after knockdown of YTHDF1. These data suggest a potential role YTHDF1 in aortic valve calcification. Conclusion This study showed that ALKBH5 attenuated aortic valve calcification through the TGFBR2/SMAD2 signaling pathway via direct m6A modification of TGFBR2. .","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"1 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCR4-targeted sensitive magnetic particle imaging for abdominal aortic aneurysm early detection and prognosis evaluation by recognizing total inflammatory cells","authors":"Genmao Cao, Ruijing Zhang, Xiaohua Jia, Jiang Bo, Yaling Li, Xuezhen Xuan, Jie Tian, Hui Hui, Shijie Xin, Honglin Dong","doi":"10.1093/cvr/cvae255","DOIUrl":"https://doi.org/10.1093/cvr/cvae255","url":null,"abstract":"Background The maximum aortic diameter remains the diagnostic criteria and the indicator for prognosis prediction of abdominal aortic aneurysms (AAA). An additional imaging modality is currently needed to help evaluate the prognosis of AAA as well as early detection of AAA formation. This study evaluated the most effective inflammatory markers for AAA using single-cell sequencing and, from these, developed probes to facilitate in vivo multimodal imaging of AAA inflammation. Methods and Results Single-cell RNA sequencing (scRNAseq) of the human aortic aneurysms, GSE155468 and GSE166676 datasets, identified CXCR4 as the most representative marker. Anti-CXCR4-PE antibody was conjugated to superparamagnetic iron oxide nanoparticles to synthesise Fe3O4-anti-CXCR4-PE probes. The biocompatibility and specificity of the probes were validated in vivo and in vitro. Magnetic particle imaging (MPI) and fluorescence imaging (FLI) were performed to assess inflammation in early and advanced AAA mouse models. CXCR4-specific receptor inhibitor, AMD3100, was used for confirming CXCR4 as an excellent target for AAA imaging and therapy. scRNAseq indicated that chemokine-related pathways were upregulated in aortic aneurysms, and CXCR4 was the chemokine receptor that markers all AAA-related immune cells and inflammatory vascular cells. Fe3O4-anti-CXCR4-PE effectively recognised immune cells and inflammatory vascular cells, as strong MPI and FLI signals corresponded to increased CXCR4, CD45, and CD68 levels which represented AAA severity and rupture risk. Importantly, Fe3O4-anti-CXCR4-PE can help identify early AAA formation when ultrasound is undiagnosable. Finally, AMD3100 treatment in AAA mouse model inhibited AAA expansion and rupture and reduced aortic wall inflammation by inhibiting accumulation of immune cells and hematopoietic stem cells. Conclusion CXCR4 markers immune cells and inflammatory vascular cells in AAA and is associated with AAA prognosis in a mouse model of AAA. CXCR4-targeting multimodal MPI/FLI provides a novel approach for AAA prognosis prediction and early detection.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"9 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NRF2 activation in the heart induces glucose metabolic reprogramming and reduces cardiac dysfunction via upregulation of the pentose phosphate pathway","authors":"Anna Zoccarato, Ioannis Smyrnias, Christina M Reumiller, Anne D Hafstad, Mei Chong, Daniel A Richards, Celio X C Santos, Asjad Visnagri, Sharwari Verma, Daniel I Bromage, Min Zhang, Xiaohong Zhang, Greta Sawyer, Richard Thompson, Ajay M Shah","doi":"10.1093/cvr/cvae250","DOIUrl":"https://doi.org/10.1093/cvr/cvae250","url":null,"abstract":"Aims The transcription factor NRF2 is well recognized as a master regulator of antioxidant responses and cytoprotective genes. Previous studies showed that NRF2 enhances resistance of mouse hearts to chronic hemodynamic overload at least in part by reducing oxidative stress. Evidence from other tissues suggests that NRF2 may modulate glucose intermediary metabolism but whether NRF2 has such effects in the heart is unclear. Here, we investigate the role of NRF2 in regulating glucose intermediary metabolism and cardiac function during disease stress. Methods and Results Cardiomyocyte-specific Keap1 knockout (csKeap1KO) mice, deficient in the endogenous inhibitor of NRF2, were used as a novel model of constitutively active NRF2 signaling. Targeted metabolomics and isotopomer analysis were employed in studies with 13C6-glucose in csKeap1KO and wild-type (WT) mice. Pharmacological and genetic approaches were utilized in neonatal rat ventricular cardiomyocytes (NRVM) to explore molecular mechanisms. We found that cardiac-specific activation of NRF2 redirected glucose metabolism towards the pentose phosphate pathway (PPP), a branch pathway of glycolysis, and mitigated pressure overload-induced cardiomyocyte death and cardiac dysfunction. Activation of NRF2 also protected against myocardial infarction-induced DNA damage in remote myocardium and cardiac dysfunction. In vitro, knockdown of Keap1 upregulated PPP enzymes and reduced cell death in NRVM subjected to chronic neurohumoral stimulation. These pro-survival effects were abolished by pharmacological inhibition of the PPP or silencing of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of NRF2 in NRVM increased stress-induced DNA damage which was rescued by supplementing the cells with either NADPH or nucleosides, the two main products of the PPP. Conclusions These results indicate that NRF2 regulates cardiac metabolic reprogramming by stimulating the diversion of glucose into the PPP, thereby generating NADPH and providing nucleotides to prevent stress-induced DNA damage and cardiac dysfunction.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"26 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}