Min Ji Cho, Byungtae Hwang, Joo Chan Lee, Young Hoon Seo, Hye Rang Park, Jangwook Lee, Nam-Kyung Lee, Wonjun Yang, Mi-Jung Kang, Yeon-Gu Kim, Sang-Yun Lee, Jang-Ho Han, Dae Soo Kim, Jeong-Ki Min, Sung Ho Park, Jong-Gil Park
{"title":"PTP4A1 alleviates angiotensin II-induced aortic aneurysmal lesions by regulating immature mural neovascularisation.","authors":"Min Ji Cho, Byungtae Hwang, Joo Chan Lee, Young Hoon Seo, Hye Rang Park, Jangwook Lee, Nam-Kyung Lee, Wonjun Yang, Mi-Jung Kang, Yeon-Gu Kim, Sang-Yun Lee, Jang-Ho Han, Dae Soo Kim, Jeong-Ki Min, Sung Ho Park, Jong-Gil Park","doi":"10.1093/cvr/cvaf224","DOIUrl":"https://doi.org/10.1093/cvr/cvaf224","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145488083","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}
Katarina Zeder,Clayton H Brown,Armella Santi,Lisa Cvirn,Silvia Ulrich,Stephan Rosenkranz,Simon Stewart,Geoff Strange,Gabor Kovacs,Bradley A Maron
AIMSPulmonary hypertension (PH) is prognostic and a potentially modifiable cause of adverse outcome across the left heart disease (LHD) spectrum. However, data on the prevalence of PH-LHD analyzed systematically using a contemporary diagnostic framework are lacking.METHODS AND RESULTSWe performed a systematic literature search including patients with heart failure with preserved or reduced ejection fraction (HFpEF, HFrEF), mitral regurgitation (MR) or aortic stenosis (AS) in three Western European countries (Austria, Germany, Switzerland; total population ∼102 Million in 2024). Studies reporting peak tricuspid regurgitation velocity (TRV) from echocardiography or mean pulmonary arterial pressure (mPAP) from right heart catheterization were included. We used a two-strata system to classify PH-LHD: 'at-risk' (TRV >2.8m/s) or 'manifest' (TRV >3.4m/s in combination with mPAP >20mmHg, to account for RHC referral bias). Meta-analysis was performed using a generalized linear mixed model.From N=123 reports including 51,333 patients, there were N=34, N=17, N=39, and N=37 studies focusing on HFpEF, HFrEF, aortic stenosis and mitral regurgitation, respectively. PH prevalence estimates based on TRV >2.8 m/s for patients with established HFpEF, HFrEF, aortic stenosis and mitral regurgitation were 62% (95%CI: 49-74%), 66% (95%CI: 57-74%), 73% (95%CI: 68-78%) and 80% (95%CI: 76-83%), respectively, and 20% (95%CI: 7-33%), 34% (95%CI: 24-43%), 38% (95%CI: 31-45%) and 54% (95%CI: 49-59%) when using TRV >3.4m/s in combination with mPAP >20mmHg, respectively. Extrapolation resulted in 2,287 (95%CI:1,770-2,804)/100,000 individuals 'at risk' and 805 (95%CI:325-1,285)/100,000 individuals with 'manifest' PH associated with heart failure (HFpEF and HFrEF combined). In addition, 712 (95%CI:637-787)/100,000 individuals and 413 (95%CI:347-480)/100,000 individuals had 'at risk' and 'manifest' PH associated with AS or MR, respectively. These collective data suggest that ∼2.7% of the population have 'at risk' and ∼1.0% 'manifest' PH-LHD in Austria, Germany and Switzerland in 2024.CONCLUSIONSThe prevalence of PH in patients with from LHD is considerable, although estimates vary by cardiac subtype and specificity of diagnostic criteria. These data warrant prospective studies emphasizing focus on PH detection and management for people with LHD, particularly heart failure.
{"title":"The prevalence of pulmonary hypertension associated with left heart disease - a systematic review and meta-analysis.","authors":"Katarina Zeder,Clayton H Brown,Armella Santi,Lisa Cvirn,Silvia Ulrich,Stephan Rosenkranz,Simon Stewart,Geoff Strange,Gabor Kovacs,Bradley A Maron","doi":"10.1093/cvr/cvaf226","DOIUrl":"https://doi.org/10.1093/cvr/cvaf226","url":null,"abstract":"AIMSPulmonary hypertension (PH) is prognostic and a potentially modifiable cause of adverse outcome across the left heart disease (LHD) spectrum. However, data on the prevalence of PH-LHD analyzed systematically using a contemporary diagnostic framework are lacking.METHODS AND RESULTSWe performed a systematic literature search including patients with heart failure with preserved or reduced ejection fraction (HFpEF, HFrEF), mitral regurgitation (MR) or aortic stenosis (AS) in three Western European countries (Austria, Germany, Switzerland; total population ∼102 Million in 2024). Studies reporting peak tricuspid regurgitation velocity (TRV) from echocardiography or mean pulmonary arterial pressure (mPAP) from right heart catheterization were included. We used a two-strata system to classify PH-LHD: 'at-risk' (TRV >2.8m/s) or 'manifest' (TRV >3.4m/s in combination with mPAP >20mmHg, to account for RHC referral bias). Meta-analysis was performed using a generalized linear mixed model.From N=123 reports including 51,333 patients, there were N=34, N=17, N=39, and N=37 studies focusing on HFpEF, HFrEF, aortic stenosis and mitral regurgitation, respectively. PH prevalence estimates based on TRV >2.8 m/s for patients with established HFpEF, HFrEF, aortic stenosis and mitral regurgitation were 62% (95%CI: 49-74%), 66% (95%CI: 57-74%), 73% (95%CI: 68-78%) and 80% (95%CI: 76-83%), respectively, and 20% (95%CI: 7-33%), 34% (95%CI: 24-43%), 38% (95%CI: 31-45%) and 54% (95%CI: 49-59%) when using TRV >3.4m/s in combination with mPAP >20mmHg, respectively. Extrapolation resulted in 2,287 (95%CI:1,770-2,804)/100,000 individuals 'at risk' and 805 (95%CI:325-1,285)/100,000 individuals with 'manifest' PH associated with heart failure (HFpEF and HFrEF combined). In addition, 712 (95%CI:637-787)/100,000 individuals and 413 (95%CI:347-480)/100,000 individuals had 'at risk' and 'manifest' PH associated with AS or MR, respectively. These collective data suggest that ∼2.7% of the population have 'at risk' and ∼1.0% 'manifest' PH-LHD in Austria, Germany and Switzerland in 2024.CONCLUSIONSThe prevalence of PH in patients with from LHD is considerable, although estimates vary by cardiac subtype and specificity of diagnostic criteria. These data warrant prospective studies emphasizing focus on PH detection and management for people with LHD, particularly heart failure.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"32 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145491681","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}
Yujun Pei, Weirui Lin, Tao Zhang, Xiangyu Chu, Han Xu, Yizhe Sun, Min Xu, Yanjiani Xu, Fangyang Huang, Di Huang, Liang Shi, Hu Zhao, Mingzhao Li, Dangfeng Zhao, Hongjia Zhang, Wenjian Jiang, Mao Chen, Jincai Luo, Changping Zhou
Aims Inflammation and the immune response are crucial factors in the progression of thoracic aortic dissection (TAD), while lymphatic vessels (LVs) play a key role in regulating the inflammatory response by facilitating the drainage of inflammatory mediators, and immune cell trafficking. Here, we investigated the role of LVs in the pathogenesis of TAD. Methods and Results Aortas collected from TAD patients and mice both showed a reduction in the number of periaortic LVs during TAD progression. Genetic linage tracing, tissue clearing technology, and fluorochrome tracers were used to explore the draining lymph nodes (LNs) of the aorta. The results demonstrated that the tracheobronchial lymph node (TLN) was the primary draining LN for the thoracic aorta. Besides, we further found that the drainage of periaortic LVs was decreased and the immune cell population in the TLN was changed in TAD. Then, lymphatic-deficient models, including genetic ablation and TLN removal, indicated that lymphatic deficiency exacerbated TAD. Furthermore, enhancing lymphangiogenesis with hVEGF-C156S treatment inhibited TAD depended on an intact lymphatic system. Mechanistically, single-cell RNA sequencing analysis showed that lymphatic endothelial cells (LECs) recruited immune cells by CXCL12-CXCR4 signaling in TAD. Importantly, blockade of CXCR4 by AMD3100 abolished the protective role of hVEGF-C156S in TAD, revealing that periaortic LVs protected against TAD progression via CXCL12-CXCR4 signaling. Finally, single-cell RNA sequencing analysis of human TAD tissue confirmed that LEC-induced immune cell recruitment played a key role in TAD. Conclusions Our findings demonstrated that the TLN and associated periaortic LVs form a functional lymphatic system, which drains the thoracic aorta and plays an inhibitory role in TAD progression, indicating that enhancing lymphatic function may represent a potential therapeutic strategy for treating TAD. Translational Perspective Our results highlight enhancing lymphatic function may be a potential therapeutic target for treating TAD.
{"title":"Periaortic lymphatic vessels protect against thoracic aortic dissection through mobilizing immune response","authors":"Yujun Pei, Weirui Lin, Tao Zhang, Xiangyu Chu, Han Xu, Yizhe Sun, Min Xu, Yanjiani Xu, Fangyang Huang, Di Huang, Liang Shi, Hu Zhao, Mingzhao Li, Dangfeng Zhao, Hongjia Zhang, Wenjian Jiang, Mao Chen, Jincai Luo, Changping Zhou","doi":"10.1093/cvr/cvaf215","DOIUrl":"https://doi.org/10.1093/cvr/cvaf215","url":null,"abstract":"Aims Inflammation and the immune response are crucial factors in the progression of thoracic aortic dissection (TAD), while lymphatic vessels (LVs) play a key role in regulating the inflammatory response by facilitating the drainage of inflammatory mediators, and immune cell trafficking. Here, we investigated the role of LVs in the pathogenesis of TAD. Methods and Results Aortas collected from TAD patients and mice both showed a reduction in the number of periaortic LVs during TAD progression. Genetic linage tracing, tissue clearing technology, and fluorochrome tracers were used to explore the draining lymph nodes (LNs) of the aorta. The results demonstrated that the tracheobronchial lymph node (TLN) was the primary draining LN for the thoracic aorta. Besides, we further found that the drainage of periaortic LVs was decreased and the immune cell population in the TLN was changed in TAD. Then, lymphatic-deficient models, including genetic ablation and TLN removal, indicated that lymphatic deficiency exacerbated TAD. Furthermore, enhancing lymphangiogenesis with hVEGF-C156S treatment inhibited TAD depended on an intact lymphatic system. Mechanistically, single-cell RNA sequencing analysis showed that lymphatic endothelial cells (LECs) recruited immune cells by CXCL12-CXCR4 signaling in TAD. Importantly, blockade of CXCR4 by AMD3100 abolished the protective role of hVEGF-C156S in TAD, revealing that periaortic LVs protected against TAD progression via CXCL12-CXCR4 signaling. Finally, single-cell RNA sequencing analysis of human TAD tissue confirmed that LEC-induced immune cell recruitment played a key role in TAD. Conclusions Our findings demonstrated that the TLN and associated periaortic LVs form a functional lymphatic system, which drains the thoracic aorta and plays an inhibitory role in TAD progression, indicating that enhancing lymphatic function may represent a potential therapeutic strategy for treating TAD. Translational Perspective Our results highlight enhancing lymphatic function may be a potential therapeutic target for treating TAD.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"145 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484729","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}
Yuze Zhang, Qiuting Dong, Xiaohui Bian, Zheng Qiao, Chuanjue Cui, Ning Yang, Jincan Liu, Rui Fu, Jun Zhang, Lei Jia, Chao Wu, Jincheng Guo, Wenhua Lin, Jingping Wang, Jiamao Fan, Yang Li, Fan Liu, Bin Yang, Xinwei Jia, Chuanyu Gao, Ming Bai, Yi He, Chengquan Han, Dong Yin, Kefei Dou
Aims Despite advancements in primary percutaneous coronary intervention (PCI), cardiac dysfunction remains a challenge in patients with ST-segment elevation myocardial infarction (STEMI). Although thymosin beta 4 has shown cardioprotective effects in preclinical MI models, its impact on chronic cardiac functional recovery post ischemia/reperfusion (I/R), especially in STEMI, warrants further investigation. This study aims to explore the therapeutic potential of recombinant human thymosin beta 4 (rhTB4) in both murine models subjected to I/R and in subjects with STEMI post-PCI. Methods and Results In C57BL/6J mice, 7-day rhTB4 treatment prevented cardiac dysfunction and fibrosis 28 days post-I/R surgery and significantly reduced plasma NT-proBNP levels at both 1 day and 28 days post-I/R. Similarly, in a permanent ligation model, rhTB4 improved cardiac function and reduced infarct size at 8 weeks post-MI. RNA-seq analysis of I/R heart tissues revealed that rhTB4 modulated the ErbB signaling pathway. In vitro hypoxia/reoxygenation models (HL-1, neonatal mouse cardiomyocytes, H9C2) demonstrated that rhTB4 activated the ErbB2/Raf1 signaling pathway, attenuated cardiomyocyte apoptosis and suppressed pro-apoptotic protein Bad expression. The cardioprotective effects of rhTB4 on cardiac function and adverse cardiac remodeling in I/R mice were abolished by ErbB2 inhibition. In a randomized, placebo-controlled, double-blind trial involving 96 STEMI patients, the infarcted areas were significantly reduced in the rhTB4 group, which received the first dose of rhTB4 within 8 hours after PCI (n=43), as compared to the placebo group at the 90-day follow-up. However, the overall differences in infarcted areas were not significantly between the rhTB4 group and the placebo group (n=96). Conclusions These findings underscore the crucial role of rhTB4 in mitigating cardiac dysfunction in an ErbB2-dependent manner. The clinical relevance of rhTB4 is demonstrated through a randomized controlled trial, emphasizing its translational potential. Further rigorous randomized studies are needed to assess the significance of early rhTB4 use post-myocardial infarction reperfusion.
{"title":"Recombinant human thymosin beta 4 improves ischemic cardiac dysfunction in mice and patients with acute ST-segment elevation myocardial infarction after reperfusion","authors":"Yuze Zhang, Qiuting Dong, Xiaohui Bian, Zheng Qiao, Chuanjue Cui, Ning Yang, Jincan Liu, Rui Fu, Jun Zhang, Lei Jia, Chao Wu, Jincheng Guo, Wenhua Lin, Jingping Wang, Jiamao Fan, Yang Li, Fan Liu, Bin Yang, Xinwei Jia, Chuanyu Gao, Ming Bai, Yi He, Chengquan Han, Dong Yin, Kefei Dou","doi":"10.1093/cvr/cvaf223","DOIUrl":"https://doi.org/10.1093/cvr/cvaf223","url":null,"abstract":"Aims Despite advancements in primary percutaneous coronary intervention (PCI), cardiac dysfunction remains a challenge in patients with ST-segment elevation myocardial infarction (STEMI). Although thymosin beta 4 has shown cardioprotective effects in preclinical MI models, its impact on chronic cardiac functional recovery post ischemia/reperfusion (I/R), especially in STEMI, warrants further investigation. This study aims to explore the therapeutic potential of recombinant human thymosin beta 4 (rhTB4) in both murine models subjected to I/R and in subjects with STEMI post-PCI. Methods and Results In C57BL/6J mice, 7-day rhTB4 treatment prevented cardiac dysfunction and fibrosis 28 days post-I/R surgery and significantly reduced plasma NT-proBNP levels at both 1 day and 28 days post-I/R. Similarly, in a permanent ligation model, rhTB4 improved cardiac function and reduced infarct size at 8 weeks post-MI. RNA-seq analysis of I/R heart tissues revealed that rhTB4 modulated the ErbB signaling pathway. In vitro hypoxia/reoxygenation models (HL-1, neonatal mouse cardiomyocytes, H9C2) demonstrated that rhTB4 activated the ErbB2/Raf1 signaling pathway, attenuated cardiomyocyte apoptosis and suppressed pro-apoptotic protein Bad expression. The cardioprotective effects of rhTB4 on cardiac function and adverse cardiac remodeling in I/R mice were abolished by ErbB2 inhibition. In a randomized, placebo-controlled, double-blind trial involving 96 STEMI patients, the infarcted areas were significantly reduced in the rhTB4 group, which received the first dose of rhTB4 within 8 hours after PCI (n=43), as compared to the placebo group at the 90-day follow-up. However, the overall differences in infarcted areas were not significantly between the rhTB4 group and the placebo group (n=96). Conclusions These findings underscore the crucial role of rhTB4 in mitigating cardiac dysfunction in an ErbB2-dependent manner. The clinical relevance of rhTB4 is demonstrated through a randomized controlled trial, emphasizing its translational potential. Further rigorous randomized studies are needed to assess the significance of early rhTB4 use post-myocardial infarction reperfusion.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"26 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498361","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}
Linsey J F Peters, Kiril Bidzhekov, Andrea Bonnin-Marquez, Sai Sahana Sundararaman, Rosanna Huchzermeier, Sanne L Maas, Kathrin Abschlag, Alexander Jans, Cheng Lin, Markus Haberbosch, Yvonne Jansen, Baixue Yu, Judith C Sluimer, Marion J Gijbels, Joachim Jankowski, Matthias Bartneck, Erik A L Biessen, Christian Weber, Yvonne Döring, Emiel P C van der Vorst
Aims Increasing evidence has shown that microRNAs (miRs) play a fundamental role in atherosclerosis, but the exact role of various miRs remains elusive. Preliminary data showed that, with a 5-fold increase, miR-26b was highly expressed in human atherosclerotic plaques compared to healthy vessels. Therefore, we aimed to determine its cell-specific effects on atherosclerosis development and its therapeutic potential. Methods and Results We examined the role of miR-26b in atherosclerosis by using whole-body Apoe-/-Mir26b-/- and myeloid cell-specific miR-26b-deficient (LysM-Cre) mice on a Western-type diet (WTD). Atherosclerotic plaque size and phenotype, as well as the phenotype and function of bone marrow-derived macrophages (BMDMs) from Apoe-/-Mir26b-/- mice, were investigated. Lipid nanoparticles (LNPs) served as vehicles for miR-26b mimics to restore miR-26b levels in miR-26b-deficient BMDMs in-vitro and in mice in-vivo. Apoe-/-Mir26b-/- mice have a striking 2.8-fold increase in atherosclerotic lesion size in the aortic arch after 12 weeks WTD, compared to control Apoe-/-, while lesions in the aortic root were unaffected. Consistent with a more advanced plaque phenotype, collagen, smooth muscle cell, and necrotic core content were all significantly increased in plaques from Apoe-/-Mir26b-/- mice, whilst the relative macrophage content was significantly reduced. This phenotype could also be observed in Apoe-/-Mir26b-/- mice after 4 weeks WTD. Intriguingly, relative plaque size in the arches of Apoe-/-LysmCre+Mir26bfl/fl mice were increased by 2.5-fold, suggesting a role for myeloid-specific miR-26b in atherosclerosis development. Further highlighting its myeloid-specific effects, Apoe-/-Mir26b-/- BMDMs showed an increase in pro-inflammatory cytokine secretion, which could be rescued by LNPs containing miR-26b mimics. MiR-26b pull-down analysis revealed AnnexinA2 as one of the novel targets playing a key role in these effects, which could be validated in BMDMs in-vitro. Furthermore, in-vivo treatment of Apoe-/-Mir26b-/- mice as well as ex-vivo treatment of human plaques with miR-26b-mimic loaded LNPs demonstrated its therapeutic potential and human relevance, respectively. Conclusion Overall, our results clearly demonstrate an atheroprotective role of miR-26b by attenuating lesion formation, mainly by suppressing inflammation and stimulating collagen breakdown. Furthermore, the therapeutic potential of miR-26b mimic loaded LNPs could be proven, opening up new avenues for miRNA-based treatment options in the future.
{"title":"MicroRNA-26b-/- augments atherosclerosis, while mimic-loaded nanoparticles reduce atherogenesis","authors":"Linsey J F Peters, Kiril Bidzhekov, Andrea Bonnin-Marquez, Sai Sahana Sundararaman, Rosanna Huchzermeier, Sanne L Maas, Kathrin Abschlag, Alexander Jans, Cheng Lin, Markus Haberbosch, Yvonne Jansen, Baixue Yu, Judith C Sluimer, Marion J Gijbels, Joachim Jankowski, Matthias Bartneck, Erik A L Biessen, Christian Weber, Yvonne Döring, Emiel P C van der Vorst","doi":"10.1093/cvr/cvaf234","DOIUrl":"https://doi.org/10.1093/cvr/cvaf234","url":null,"abstract":"Aims Increasing evidence has shown that microRNAs (miRs) play a fundamental role in atherosclerosis, but the exact role of various miRs remains elusive. Preliminary data showed that, with a 5-fold increase, miR-26b was highly expressed in human atherosclerotic plaques compared to healthy vessels. Therefore, we aimed to determine its cell-specific effects on atherosclerosis development and its therapeutic potential. Methods and Results We examined the role of miR-26b in atherosclerosis by using whole-body Apoe-/-Mir26b-/- and myeloid cell-specific miR-26b-deficient (LysM-Cre) mice on a Western-type diet (WTD). Atherosclerotic plaque size and phenotype, as well as the phenotype and function of bone marrow-derived macrophages (BMDMs) from Apoe-/-Mir26b-/- mice, were investigated. Lipid nanoparticles (LNPs) served as vehicles for miR-26b mimics to restore miR-26b levels in miR-26b-deficient BMDMs in-vitro and in mice in-vivo. Apoe-/-Mir26b-/- mice have a striking 2.8-fold increase in atherosclerotic lesion size in the aortic arch after 12 weeks WTD, compared to control Apoe-/-, while lesions in the aortic root were unaffected. Consistent with a more advanced plaque phenotype, collagen, smooth muscle cell, and necrotic core content were all significantly increased in plaques from Apoe-/-Mir26b-/- mice, whilst the relative macrophage content was significantly reduced. This phenotype could also be observed in Apoe-/-Mir26b-/- mice after 4 weeks WTD. Intriguingly, relative plaque size in the arches of Apoe-/-LysmCre+Mir26bfl/fl mice were increased by 2.5-fold, suggesting a role for myeloid-specific miR-26b in atherosclerosis development. Further highlighting its myeloid-specific effects, Apoe-/-Mir26b-/- BMDMs showed an increase in pro-inflammatory cytokine secretion, which could be rescued by LNPs containing miR-26b mimics. MiR-26b pull-down analysis revealed AnnexinA2 as one of the novel targets playing a key role in these effects, which could be validated in BMDMs in-vitro. Furthermore, in-vivo treatment of Apoe-/-Mir26b-/- mice as well as ex-vivo treatment of human plaques with miR-26b-mimic loaded LNPs demonstrated its therapeutic potential and human relevance, respectively. Conclusion Overall, our results clearly demonstrate an atheroprotective role of miR-26b by attenuating lesion formation, mainly by suppressing inflammation and stimulating collagen breakdown. Furthermore, the therapeutic potential of miR-26b mimic loaded LNPs could be proven, opening up new avenues for miRNA-based treatment options in the future.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"22 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498363","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}
Since the 1950s, when Ancel Keys popularized the traditional Mediterranean diet, an immense accrual of large and valid studies, including prospective cohort studies, randomized controlled trials (RCT), and systematic reviews, have been conducted to investigate the potential health benefits related to this dietary pattern. The available evidence shows that the traditional Mediterranean diet represents a sustainable, healthy, and highly palatable pattern with a wide array of associated health benefits. In particular, its protective effects on cardiovascular disease have been supported by several consistent large RCTs, namely, the Lyon Diet-Heart Study, PREDIMED, PREDIMED-Plus and CORDIOPREV. The traditional Mediterranean diet is not a vegetarian diet, but it emphasizes the preferential consumption of minimally processed plant-based foods: fruits, vegetables, whole-grain cereals, legumes, and tree nuts. Its unique components -different from other healthy, plant-based, food patterns- are extra virgin olive oil as the main source of fat (keeping a high monounsaturated-to-saturated fat ratio), a high consumption of tree nuts, and low-to-moderate consumption of red wine with meals. However, the inclusion of an alcoholic beverage in a healthy diet is becoming increasingly controversial. An ongoing RCT, the University of Navarra Alumni Trialist Initiative (UNATI), aims to answer this question in 10,000 drinkers. In addition to conventional epidemiologic studies, metabolomics techniques have been applied to assess the role of adherence to the Mediterranean diet and to better understand the mechanisms involved in the protection afforded by this interesting dietary pattern. In this review we update the available scientific evidence.
{"title":"The Mediterranean diet and cardiovascular disease.","authors":"María Barbería-Latasa,Miguel A Martínez-González","doi":"10.1093/cvr/cvaf218","DOIUrl":"https://doi.org/10.1093/cvr/cvaf218","url":null,"abstract":"Since the 1950s, when Ancel Keys popularized the traditional Mediterranean diet, an immense accrual of large and valid studies, including prospective cohort studies, randomized controlled trials (RCT), and systematic reviews, have been conducted to investigate the potential health benefits related to this dietary pattern. The available evidence shows that the traditional Mediterranean diet represents a sustainable, healthy, and highly palatable pattern with a wide array of associated health benefits. In particular, its protective effects on cardiovascular disease have been supported by several consistent large RCTs, namely, the Lyon Diet-Heart Study, PREDIMED, PREDIMED-Plus and CORDIOPREV. The traditional Mediterranean diet is not a vegetarian diet, but it emphasizes the preferential consumption of minimally processed plant-based foods: fruits, vegetables, whole-grain cereals, legumes, and tree nuts. Its unique components -different from other healthy, plant-based, food patterns- are extra virgin olive oil as the main source of fat (keeping a high monounsaturated-to-saturated fat ratio), a high consumption of tree nuts, and low-to-moderate consumption of red wine with meals. However, the inclusion of an alcoholic beverage in a healthy diet is becoming increasingly controversial. An ongoing RCT, the University of Navarra Alumni Trialist Initiative (UNATI), aims to answer this question in 10,000 drinkers. In addition to conventional epidemiologic studies, metabolomics techniques have been applied to assess the role of adherence to the Mediterranean diet and to better understand the mechanisms involved in the protection afforded by this interesting dietary pattern. In this review we update the available scientific evidence.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"59 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477697","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}
Aims Vascular remodeling plays a crucial role in the pathogenesis of vascular diseases. Our previous research highlighted the significance of RNA-binding protein 24 (RBM24) in the pathogenesis of dilated cardiomyopathy and the development of the zebrafish circulatory system. However, the specific role of RBM24 in vascular remodeling and its underlying mechanisms remain unclear. This study aims to elucidate the role of RBM24 in vascular remodeling and explore its associated signaling pathways as potential therapeutic targets. Methods and Results We established human (in vitro) and mouse (in vivo) vascular injury models to identify the regulatory role of RBM24 in vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling. mRNA stability assays, RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to explore the underlying mechanisms. RBM24 was significantly upregulated in injured mouse carotid arteries and platelet-derived growth factor (PDGF)-stimulated human VSMCs. VSMC-specific knockout of Rbm24 in mice attenuated injury-induced vascular remodeling, evidenced by reduced neointima formation, increased contractile markers and decreased synthetic and proliferative markers. Conversely, AAV-mediated RBM24 overexpression promoted vascular remodeling. Further, the silencing of RBM24 in human VSMCs suppressed VSMC phenotypic switching, as indicated by reduced proliferation and migration, increased expression of contractile markers, and decreased synthetic and proliferative markers, whereas RBM24 overexpression had the opposite effect. Mechanistically, RBM24 stabilized Janus kinase 2 (JAK2) mRNA, promoting its translation and enhancing the JAK2-Signal transducer and activator of transcription 3 (STAT3)- Krüppel-like factor 4 (KLF4) signaling axis to drive VSMC phenotypic switching and vascular remodeling. Furthermore, STAT3 inhibition via shRNA or Nifuroxazide effectively suppressed VSMC phenotypic switching and injury-induced vascular remodeling. Conclusions This study demonstrates that RBM24 promotes vascular remodeling by stabilizing JAK2 mRNA and enhancing the JAK2-STAT3-KLF4 signaling axis. Targeting RBM24 and its associated pathways may offer novel therapeutic strategies against vascular remodeling.
目的血管重构在血管疾病的发病机制中起着至关重要的作用。我们之前的研究强调了rna结合蛋白24 （RBM24）在扩张型心肌病发病机制和斑马鱼循环系统发育中的重要意义。然而，RBM24在血管重构中的具体作用及其潜在机制尚不清楚。本研究旨在阐明RBM24在血管重构中的作用，并探索其相关信号通路作为潜在的治疗靶点。方法与结果建立人（体外）和小鼠（体内）血管损伤模型，研究RBM24在血管平滑肌细胞（VSMC）表型转换和血管重构中的调节作用。采用mRNA稳定性测定、RNA免疫沉淀（RIP）和荧光素酶报告基因测定来探索其潜在机制。RBM24在损伤小鼠颈动脉和血小板衍生生长因子（PDGF）刺激的人VSMCs中显著上调。小鼠vsmc特异性敲除Rbm24可减轻损伤诱导的血管重构，新内膜形成减少，收缩标记物增加，合成和增殖标记物减少。相反，aav介导的RBM24过表达促进血管重构。此外，RBM24在人VSMC中的沉默抑制了VSMC的表型转换，表明增殖和迁移减少，收缩标记表达增加，合成和增殖标记减少，而RBM24过表达则具有相反的作用。机制上，RBM24稳定了Janus kinase 2 (JAK2) mRNA，促进其翻译，增强JAK2- signal transducer and activator of transcription 3 (STAT3)- kr pel-like factor 4 （KLF4）信号轴，驱动VSMC表型转换和血管重构。此外，通过shRNA或Nifuroxazide抑制STAT3可有效抑制VSMC表型转换和损伤诱导的血管重构。结论RBM24通过稳定JAK2 mRNA和增强JAK2- stat3 - klf4信号轴促进血管重构。靶向RBM24及其相关通路可能为血管重构提供新的治疗策略。
{"title":"RBM24 regulates phenotypic switching of smooth muscle cell in vascular remodeling by stabilizing JAK2 mRNA","authors":"Huawei Zhang, Jing Liu, Daqian Sun, Yuxiu Liu, Wenhao Sun, Shanshan Wang, Xiuqin Xu","doi":"10.1093/cvr/cvaf219","DOIUrl":"https://doi.org/10.1093/cvr/cvaf219","url":null,"abstract":"Aims Vascular remodeling plays a crucial role in the pathogenesis of vascular diseases. Our previous research highlighted the significance of RNA-binding protein 24 (RBM24) in the pathogenesis of dilated cardiomyopathy and the development of the zebrafish circulatory system. However, the specific role of RBM24 in vascular remodeling and its underlying mechanisms remain unclear. This study aims to elucidate the role of RBM24 in vascular remodeling and explore its associated signaling pathways as potential therapeutic targets. Methods and Results We established human (in vitro) and mouse (in vivo) vascular injury models to identify the regulatory role of RBM24 in vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling. mRNA stability assays, RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to explore the underlying mechanisms. RBM24 was significantly upregulated in injured mouse carotid arteries and platelet-derived growth factor (PDGF)-stimulated human VSMCs. VSMC-specific knockout of Rbm24 in mice attenuated injury-induced vascular remodeling, evidenced by reduced neointima formation, increased contractile markers and decreased synthetic and proliferative markers. Conversely, AAV-mediated RBM24 overexpression promoted vascular remodeling. Further, the silencing of RBM24 in human VSMCs suppressed VSMC phenotypic switching, as indicated by reduced proliferation and migration, increased expression of contractile markers, and decreased synthetic and proliferative markers, whereas RBM24 overexpression had the opposite effect. Mechanistically, RBM24 stabilized Janus kinase 2 (JAK2) mRNA, promoting its translation and enhancing the JAK2-Signal transducer and activator of transcription 3 (STAT3)- Krüppel-like factor 4 (KLF4) signaling axis to drive VSMC phenotypic switching and vascular remodeling. Furthermore, STAT3 inhibition via shRNA or Nifuroxazide effectively suppressed VSMC phenotypic switching and injury-induced vascular remodeling. Conclusions This study demonstrates that RBM24 promotes vascular remodeling by stabilizing JAK2 mRNA and enhancing the JAK2-STAT3-KLF4 signaling axis. Targeting RBM24 and its associated pathways may offer novel therapeutic strategies against vascular remodeling.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"43 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145484738","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}
Milind Y Desai, Sherif F Nagueh, John R Giudicessi, Michael J Previs, Danielle Kellner, Matthew J Pollman, Fatbardha Varfaj, Laura A Robertson, Natasha Sonicheva-Paterson, Richard Pushkin, Brian Mangal, LaTanya Tomlinson, William G Harrison, Lynn Yamamoto, Gretchen Argast, Laura M Lombardi, Kathryn N Ivey, Whittemore G Tingley
This brief report details the initial findings from a Phase 1b/2 trial of TN-201, an adeno-associated virus serotype 9 (AAV9) gene therapy for MYBPC3-associated hypertrophic cardiomyopathy (HCM), a condition with significant morbidity, increased risk of mortality, and no approved therapy for the majority of patients. TN-201 was well tolerated, and changes to the management of potential immune responses resulted in a shorter period of immunosuppression. These results show consistent transduction and expression of TN-201 in cardiomyocytes, corresponding with increases in MyBP-C levels, reductions or stabilization of cardiac biomarkers, and reductions in key measures of left ventricular (LV) hypertrophy.
{"title":"First-in-human study of TN-201, an AAV9 gene replacement therapy in MYBPC3 -associated hypertrophic cardiomyopathy: initial safety, pharmacodynamic, and imaging results from MyPEAK-1","authors":"Milind Y Desai, Sherif F Nagueh, John R Giudicessi, Michael J Previs, Danielle Kellner, Matthew J Pollman, Fatbardha Varfaj, Laura A Robertson, Natasha Sonicheva-Paterson, Richard Pushkin, Brian Mangal, LaTanya Tomlinson, William G Harrison, Lynn Yamamoto, Gretchen Argast, Laura M Lombardi, Kathryn N Ivey, Whittemore G Tingley","doi":"10.1093/cvr/cvaf200","DOIUrl":"https://doi.org/10.1093/cvr/cvaf200","url":null,"abstract":"This brief report details the initial findings from a Phase 1b/2 trial of TN-201, an adeno-associated virus serotype 9 (AAV9) gene therapy for MYBPC3-associated hypertrophic cardiomyopathy (HCM), a condition with significant morbidity, increased risk of mortality, and no approved therapy for the majority of patients. TN-201 was well tolerated, and changes to the management of potential immune responses resulted in a shorter period of immunosuppression. These results show consistent transduction and expression of TN-201 in cardiomyocytes, corresponding with increases in MyBP-C levels, reductions or stabilization of cardiac biomarkers, and reductions in key measures of left ventricular (LV) hypertrophy.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"161 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472748","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}
Jinlong Pang, Lei pan, Wei Shen, Gangsi Yi, Xu Kong, Heqiang Zhang, Baolong Feng, Hu Sun, Liangcai Chen, Guiyang Li, Hui Zhuang, Jiajin Chen, Lin Lu, Yan Wang, Lingjun Jie, Yanhui Zhang
Aims Vascular ageing (VA), characterised by vascular endothelial dysfunction, is a major contributor to age-related chronic conditions. Leucine-rich repeat-containing protein 8A (LRRC8A) is vital in maintaining vascular endothelial function; however, the role of endothelial LRRC8A in VA is undefined. We aimed to investigate the role and mechanism of endothelial LRRC8A in VA. Methods and results We found that LRRC8A expression was clearly downregulated in the aged murine aortas. Further integrated analysis of single-cell and bulk RNA-seq and experimental verification revealed that endothelial LRRC8A governed VA by counteracting cell cycle, cellular senescence and oxidative stress. Additionally, endothelial LRRC8A deletion exacerbated the D-galactose (D-gal)-induced VA progression. Mechanistically, endothelial LRRC8A phosphorylated AMPK at T172 and subsequently facilitated SIRT1 nuclear translocation, ultimately counteracting the p53-dependent senescence pathway and activating the FOXO3-dependent antioxidant pathway. Therapeutically, pharmacological agonists of AMPK and SIRT1 effectively rescued endothelial cell senescence and VA in the context of endothelial LRRC8A deficiency. Additionally, endothelial-targeted adeno-associated virus (AAV)-LRRC8A gene therapy can effectively delay the progression of VA in naturally ageing mice. Conclusions Our findings provide the first evidence supporting endothelial LRRC8A as a novel modulator of the AMPK-SIRT1 axis and suggest that targeting LRRC8A represents a promising therapeutic strategy for VA and age-related chronic conditions.
{"title":"Endothelial LRRC8A delays vascular ageing in natural and accelerated ageing mouse models","authors":"Jinlong Pang, Lei pan, Wei Shen, Gangsi Yi, Xu Kong, Heqiang Zhang, Baolong Feng, Hu Sun, Liangcai Chen, Guiyang Li, Hui Zhuang, Jiajin Chen, Lin Lu, Yan Wang, Lingjun Jie, Yanhui Zhang","doi":"10.1093/cvr/cvaf212","DOIUrl":"https://doi.org/10.1093/cvr/cvaf212","url":null,"abstract":"Aims Vascular ageing (VA), characterised by vascular endothelial dysfunction, is a major contributor to age-related chronic conditions. Leucine-rich repeat-containing protein 8A (LRRC8A) is vital in maintaining vascular endothelial function; however, the role of endothelial LRRC8A in VA is undefined. We aimed to investigate the role and mechanism of endothelial LRRC8A in VA. Methods and results We found that LRRC8A expression was clearly downregulated in the aged murine aortas. Further integrated analysis of single-cell and bulk RNA-seq and experimental verification revealed that endothelial LRRC8A governed VA by counteracting cell cycle, cellular senescence and oxidative stress. Additionally, endothelial LRRC8A deletion exacerbated the D-galactose (D-gal)-induced VA progression. Mechanistically, endothelial LRRC8A phosphorylated AMPK at T172 and subsequently facilitated SIRT1 nuclear translocation, ultimately counteracting the p53-dependent senescence pathway and activating the FOXO3-dependent antioxidant pathway. Therapeutically, pharmacological agonists of AMPK and SIRT1 effectively rescued endothelial cell senescence and VA in the context of endothelial LRRC8A deficiency. Additionally, endothelial-targeted adeno-associated virus (AAV)-LRRC8A gene therapy can effectively delay the progression of VA in naturally ageing mice. Conclusions Our findings provide the first evidence supporting endothelial LRRC8A as a novel modulator of the AMPK-SIRT1 axis and suggest that targeting LRRC8A represents a promising therapeutic strategy for VA and age-related chronic conditions.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"377 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472879","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}
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