Pub Date : 2025-08-12DOI: 10.1016/j.jacbts.2025.101347
Daphne Moutsoglou MD, PhD , Madelyn Blake BS , Dina C. Belhasan MD , Gretchen Peichel BAN , Brenda M. Vang AAS , E. Kenneth Weir MD , Sharon Lopez BS , Kurt W. Prins MD, PhD , Amanda J. Kabage MS , Sasha Z. Prisco MD, PhD , Benjamin P. Kremer BS , Alexander Khoruts MD, MS , Thenappan Thenappan MD
Pulmonary arterial hypertension (PAH) is a complex inflammatory disease that the gut microbiome likely contributes to and may be a potential therapeutic avenue for nontoxically improving outcomes. Here, we show that microbiota transplant therapy (MTT) is safe and feasible. The MTT regimen achieves only modest levels of donor microbiota engraftment but is accompanied by a transient reduction in circulating pro-inflammatory cytokines. These findings of decreased systemic inflammation with only modest donor engraftment support the potential of MTT as a novel treatment for PAH. (Microbiota Transplant Therapy for Pulmonary Arterial Hypertension: Early Safety and Feasibility Study; NCT04884971)
{"title":"Microbiota Transplant Therapy Is Safe and Feasible in Pulmonary Arterial Hypertension","authors":"Daphne Moutsoglou MD, PhD , Madelyn Blake BS , Dina C. Belhasan MD , Gretchen Peichel BAN , Brenda M. Vang AAS , E. Kenneth Weir MD , Sharon Lopez BS , Kurt W. Prins MD, PhD , Amanda J. Kabage MS , Sasha Z. Prisco MD, PhD , Benjamin P. Kremer BS , Alexander Khoruts MD, MS , Thenappan Thenappan MD","doi":"10.1016/j.jacbts.2025.101347","DOIUrl":"10.1016/j.jacbts.2025.101347","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is a complex inflammatory disease that the gut microbiome likely contributes to and may be a potential therapeutic avenue for nontoxically improving outcomes. Here, we show that microbiota transplant therapy (MTT) is safe and feasible. The MTT regimen achieves only modest levels of donor microbiota engraftment but is accompanied by a transient reduction in circulating pro-inflammatory cytokines. These findings of decreased systemic inflammation with only modest donor engraftment support the potential of MTT as a novel treatment for PAH. (Microbiota Transplant Therapy for Pulmonary Arterial Hypertension: Early Safety and Feasibility Study; <span><span>NCT04884971</span><svg><path></path></svg></span>)</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101347"},"PeriodicalIF":8.4,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829911","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}
Pub Date : 2025-08-11DOI: 10.1016/j.jacbts.2025.101357
Chae-Myeong Ha PhD, Adam R. Wende PhD
{"title":"Cracking the Code of a Preclinical Rodent Model of HFpEF","authors":"Chae-Myeong Ha PhD, Adam R. Wende PhD","doi":"10.1016/j.jacbts.2025.101357","DOIUrl":"10.1016/j.jacbts.2025.101357","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101357"},"PeriodicalIF":8.4,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144809871","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}
Pub Date : 2025-08-06DOI: 10.1016/j.jacbts.2025.101358
Harvey G. Roweth PhD
{"title":"Primed to Fail","authors":"Harvey G. Roweth PhD","doi":"10.1016/j.jacbts.2025.101358","DOIUrl":"10.1016/j.jacbts.2025.101358","url":null,"abstract":"","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101358"},"PeriodicalIF":8.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144781253","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}
Pub Date : 2025-08-05DOI: 10.1016/j.jacbts.2025.101355
Constance C.F.M.J. Baaten PhD , Julia Wollenhaupt PhD , Tobias M. Henning MD , Sonja Vondenhoff MS , Jonas R. Schröer MD , Eleni Stamellou MD, PhD, MS , Turgay Saritas MD, PhD , Berkan Kurt MD , Leonard Boger MD , Alessandra Antwerpen , Juliane Hermann PhD , Magdolna Nagy PhD , Marieke Sternkopf PhD , Eva Miriam Buhl PhD , Ute Raffetseder PhD , Paola E.J. van der Meijden PhD , Marijke J.E. Kuijpers PhD , Henri M.H. Spronk PhD , Stefan J. Schunk MD , Joachim Jankowski PhD , Heidi Noels PhD
Patients with chronic kidney disease (CKD) are at increased risk of thrombotic and hemorrhagic complications. Findings on platelet defects in CKD are conflicting. Therefore, we examined platelet function in CKD stage 3 to 5 dialysis patients without antithrombotic therapy, in CKD5D/hemodialysis patients on acetylsalicylic acid (ASA) as well as in a CKD mouse model. Patients with advanced CKD without antithrombotic therapy show platelet preactivation with a partial secondary platelet dysfunction mainly upon collagen/GPVI stimulation. Platelets from hemodialysis patients on ASA showed a less severe CKD-associated secondary platelet dysfunction compared with those not taking ASA, with comparable observations in CKD mice on ASA vs vehicle.
{"title":"Impaired Secondary Platelet Response in Chronic Kidney Disease as a Consequence of Prior Platelet Activation","authors":"Constance C.F.M.J. Baaten PhD , Julia Wollenhaupt PhD , Tobias M. Henning MD , Sonja Vondenhoff MS , Jonas R. Schröer MD , Eleni Stamellou MD, PhD, MS , Turgay Saritas MD, PhD , Berkan Kurt MD , Leonard Boger MD , Alessandra Antwerpen , Juliane Hermann PhD , Magdolna Nagy PhD , Marieke Sternkopf PhD , Eva Miriam Buhl PhD , Ute Raffetseder PhD , Paola E.J. van der Meijden PhD , Marijke J.E. Kuijpers PhD , Henri M.H. Spronk PhD , Stefan J. Schunk MD , Joachim Jankowski PhD , Heidi Noels PhD","doi":"10.1016/j.jacbts.2025.101355","DOIUrl":"10.1016/j.jacbts.2025.101355","url":null,"abstract":"<div><div>Patients with chronic kidney disease (CKD) are at increased risk of thrombotic and hemorrhagic complications. Findings on platelet defects in CKD are conflicting. Therefore, we examined platelet function in CKD stage 3 to 5 dialysis patients without antithrombotic therapy, in CKD5D/hemodialysis patients on acetylsalicylic acid (ASA) as well as in a CKD mouse model. Patients with advanced CKD without antithrombotic therapy show platelet preactivation with a partial secondary platelet dysfunction mainly upon collagen/GPVI stimulation. Platelets from hemodialysis patients on ASA showed a less severe CKD-associated secondary platelet dysfunction compared with those not taking ASA, with comparable observations in CKD mice on ASA vs vehicle.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101355"},"PeriodicalIF":8.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780540","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}
Pub Date : 2025-08-05DOI: 10.1016/j.jacbts.2025.101353
Zhen Zhou MD , Pujun Guan PhD , Ripon Sarkar PhD , Yang Yu MD , Alexis Richard PhD , Dar Weiss PhD , Yuki Kawamura PhD , Chen Zhang MD , Yanming Li PhD , Tomas Vaisar PhD , Daniel R. Martin PhD , L. Maximillian Buja MD , Zhouxuan Li PhD , Kartik Venkatachalam PhD , Ying H. Shen MD, PhD , Scott A. LeMaire MD , Jay D. Humphrey PhD , Dianna M. Milewicz MD, PhD
Dysfunctional mechanosensing via focal adhesions (FAs) significantly contributes to thoracic aortic dissection in the β-aminopropionitrile mouse model by triggering FA kinase activation and subsequent Rho/ROCK and mTOR signaling pathways. The present findings indicate that these signaling pathways play distinct roles in ascending vs descending dissections. Specifically, in the ascending aorta, smooth muscle cell FA kinase–Rho/ROCK signaling acts as a beneficial adaptive mechanism to prevent dissections, whereas mTOR signaling is pathogenic and contributes to dissections.
{"title":"Focal Adhesion Kinase Drives Rho/ROCK and mTOR Signaling to Protect and Augment Aortic Dissections","authors":"Zhen Zhou MD , Pujun Guan PhD , Ripon Sarkar PhD , Yang Yu MD , Alexis Richard PhD , Dar Weiss PhD , Yuki Kawamura PhD , Chen Zhang MD , Yanming Li PhD , Tomas Vaisar PhD , Daniel R. Martin PhD , L. Maximillian Buja MD , Zhouxuan Li PhD , Kartik Venkatachalam PhD , Ying H. Shen MD, PhD , Scott A. LeMaire MD , Jay D. Humphrey PhD , Dianna M. Milewicz MD, PhD","doi":"10.1016/j.jacbts.2025.101353","DOIUrl":"10.1016/j.jacbts.2025.101353","url":null,"abstract":"<div><div>Dysfunctional mechanosensing via focal adhesions (FAs) significantly contributes to thoracic aortic dissection in the β-aminopropionitrile mouse model by triggering FA kinase activation and subsequent Rho/ROCK and mTOR signaling pathways. The present findings indicate that these signaling pathways play distinct roles in ascending vs descending dissections. Specifically, in the ascending aorta, smooth muscle cell FA kinase–Rho/ROCK signaling acts as a beneficial adaptive mechanism to prevent dissections, whereas mTOR signaling is pathogenic and contributes to dissections.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 9","pages":"Article 101353"},"PeriodicalIF":8.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144771792","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.02.016
Lan Gao PhD , Qindong Shi PhD , Bin Sun MD , Xiaoyu Zhang MD , Peiying Zheng MD , Linjing Zhou MD , Gang Tian PhD , Hao Li PhD
This study investigates the role of c-FLIP in sepsis-induced myocardial dysfunction (SIMD), focusing on cardiac microcirculation and mitochondrial autophagy. Using SIMD rat and LPS-induced cardiac microvascular endothelial cell injury models, we found that c-FLIP deficiency disrupts mitochondrial homeostasis, exacerbating microcirculatory damage. c-FLIP differentially regulates mitochondrial autophagy via FUNDC1. Overexpression of c-FLIP balances autophagy, protects mitochondria, reduces inflammation, and ameliorates SIMD, highlighting its potential as a therapeutic target.
{"title":"c-FLIP Protects Cardiac Microcirculation in Sepsis-Induced Myocardial Dysfunction Via FUNDC1-Mediated Regulation of Mitochondrial Autophagy","authors":"Lan Gao PhD , Qindong Shi PhD , Bin Sun MD , Xiaoyu Zhang MD , Peiying Zheng MD , Linjing Zhou MD , Gang Tian PhD , Hao Li PhD","doi":"10.1016/j.jacbts.2025.02.016","DOIUrl":"10.1016/j.jacbts.2025.02.016","url":null,"abstract":"<div><div>This study investigates the role of c-FLIP in sepsis-induced myocardial dysfunction (SIMD), focusing on cardiac microcirculation and mitochondrial autophagy. Using SIMD rat and LPS-induced cardiac microvascular endothelial cell injury models, we found that c-FLIP deficiency disrupts mitochondrial homeostasis, exacerbating microcirculatory damage. c-FLIP differentially regulates mitochondrial autophagy via FUNDC1. Overexpression of c-FLIP balances autophagy, protects mitochondria, reduces inflammation, and ameliorates SIMD, highlighting its potential as a therapeutic target.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101257"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078023","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.03.005
Jun-Zhuo Shi MS , Yong-Jian Zhu MD , Meng-Jie Zhang BS , Yi Yan PhD , Lu-Ling Zhao MS , Hong-Da Zhang MD , Yan Liu MD , Wen-Hui Wu PhD , Zhe Cheng MD , Chun-Guang Qiu MD , Jie-Jian Kou MS , Yun-Feng Zhou PhD , Xiao-Bin Pang PhD , Ji-Wang Chen MD , Xin-Mei Xie MS , Yang-Yang He PhD , Zhi-Cheng Jing MD
Uric acid metabolism is implicated in the pathogenesis of pulmonary arterial hypertension, wherein the key metabolite hypoxanthine exhibits elevated levels, thereby promoting pulmonary vascular remodeling through facilitation of cell proliferation and migration as well as regulation of adenosine triphosphate binding cassette transport signaling pathway. Consequently, therapeutic interventions targeting hypoxanthine synthesis may hold promise for the management of pulmonary arterial hypertension.
{"title":"Hypoxanthine Promotes Pulmonary Vascular Remodeling and Adenosine Deaminase Is a Therapeutic Target for Pulmonary Hypertension","authors":"Jun-Zhuo Shi MS , Yong-Jian Zhu MD , Meng-Jie Zhang BS , Yi Yan PhD , Lu-Ling Zhao MS , Hong-Da Zhang MD , Yan Liu MD , Wen-Hui Wu PhD , Zhe Cheng MD , Chun-Guang Qiu MD , Jie-Jian Kou MS , Yun-Feng Zhou PhD , Xiao-Bin Pang PhD , Ji-Wang Chen MD , Xin-Mei Xie MS , Yang-Yang He PhD , Zhi-Cheng Jing MD","doi":"10.1016/j.jacbts.2025.03.005","DOIUrl":"10.1016/j.jacbts.2025.03.005","url":null,"abstract":"<div><div>Uric acid metabolism is implicated in the pathogenesis of pulmonary arterial hypertension, wherein the key metabolite hypoxanthine exhibits elevated levels, thereby promoting pulmonary vascular remodeling through facilitation of cell proliferation and migration as well as regulation of adenosine triphosphate binding cassette transport signaling pathway. Consequently, therapeutic interventions targeting hypoxanthine synthesis may hold promise for the management of pulmonary arterial hypertension.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101273"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896126","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}
Pub Date : 2025-08-01DOI: 10.1016/j.jacbts.2025.02.021
María Valero-Muñoz PhD, Eng Leng Saw PhD, Hannah Cooper BA, David R. Pimentel MD, Flora Sam MD
Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction (HFpEF). Increased adiposity is implicated in its pathophysiology. We investigated changes in white adipose tissue (WAT) in obesity-associated HFpEF utilizing patient samples and a murine model of obesity-associated HFpEF. WAT analysis revealed "browning", characterized by smaller adipocytes and increased UCP1 expression, alongside fibrosis and reduced vascular markers during acute HF decompensation. During chronic, stable HFpEF, “browning” markers declined. There is a dynamic process in WAT, where acute HF exacerbations trigger transient “browning”, fibrosis, and vascular deterioration, which partially reverse but fibrosis persists. WAT dysfunction worsens during acute HF, highlighting a potential therapeutic target for obesity-related HFpEF.
{"title":"White Adipose Tissue in Obesity-Associated HFpEF","authors":"María Valero-Muñoz PhD, Eng Leng Saw PhD, Hannah Cooper BA, David R. Pimentel MD, Flora Sam MD","doi":"10.1016/j.jacbts.2025.02.021","DOIUrl":"10.1016/j.jacbts.2025.02.021","url":null,"abstract":"<div><div>Obesity and hypertension are prevalent comorbidities in heart failure with preserved ejection fraction (HFpEF). Increased adiposity is implicated in its pathophysiology. We investigated changes in white adipose tissue (WAT) in obesity-associated HFpEF utilizing patient samples and a murine model of obesity-associated HFpEF. WAT analysis revealed \"browning\", characterized by smaller adipocytes and increased UCP1 expression, alongside fibrosis and reduced vascular markers during acute HF decompensation. During chronic, stable HFpEF, “browning” markers declined. There is a dynamic process in WAT, where acute HF exacerbations trigger transient “browning”, fibrosis, and vascular deterioration, which partially reverse but fibrosis persists. WAT dysfunction worsens during acute HF, highlighting a potential therapeutic target for obesity-related HFpEF.</div></div>","PeriodicalId":14831,"journal":{"name":"JACC: Basic to Translational Science","volume":"10 8","pages":"Article 101262"},"PeriodicalIF":8.4,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019452","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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