Yasuki Nakada, Allen Sam Titus, Wataru Mizushima, Yanfei Yang, Peiyong Zhai, Yimin Tian, Shinichi Oka, Toshihide Kashihara, Nadezhda Fefelova, Sri Harika Pamarthi, Tong Liu, Hong Li, Lai-Hua Xie, Koichiro Takayama, Soichiro Ikeda, Masato Matsushita, Chun Yang Huang, Chiao-Po Hsu, Kenji Onoue, Yoshihiko Saito, Junichi Sadoshima
{"title":"p22phox prevents the oxidation of SERCA2a and stabilizes it in the heart","authors":"Yasuki Nakada, Allen Sam Titus, Wataru Mizushima, Yanfei Yang, Peiyong Zhai, Yimin Tian, Shinichi Oka, Toshihide Kashihara, Nadezhda Fefelova, Sri Harika Pamarthi, Tong Liu, Hong Li, Lai-Hua Xie, Koichiro Takayama, Soichiro Ikeda, Masato Matsushita, Chun Yang Huang, Chiao-Po Hsu, Kenji Onoue, Yoshihiko Saito, Junichi Sadoshima","doi":"10.1038/s44161-025-00699-x","DOIUrl":"10.1038/s44161-025-00699-x","url":null,"abstract":"Sarcoplasmic/endoplasmic reticulum (SR/ER) Ca2+ ATPase 2a (SERCA2a) mediates Ca2+ reuptake into the SR in cardiomyocytes. The inactivation or downregulation of SERCA2a leads to reduced contractility in the failing heart. Here we show that SERCA2a is regulated by p22phox, a heterodimeric partner of NADPH oxidases. Endogenous p22phox was upregulated by pressure overload, but cardiac-specific p22phox knockout (cKO) in mice exacerbated heart failure, enhanced the downregulation of SERCA2a and increased oxidative stress in the SR. We show that p22phox interacts with SERCA2a, preventing its oxidation at Cys498 and subsequent degradation by the Smurf1 and Hrd1 E3 ubiquitin ligases. The exacerbation of SERCA2a downregulation and cardiac dysfunction following pressure overload in p22phox cKO mice was alleviated when these mice were crossed with SERCA2a-C498S knock-in mice, in which the oxidation-susceptible and degradation-promoting cysteine residue is mutated. Future molecular interventions to prevent the oxidation of SERCA2a at Cys498 may prevent its downregulation during heart failure. Nakada, Titus et al. show that p22phox, a heterodimeric partner of NADPH oxidases, prevents sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) oxidation at Cys498 and its downregulation. This study suggests that therapeutic interventions to protect this residue may sustain SERCA2a expression in heart failure.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1187-1205"},"PeriodicalIF":10.8,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144994610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Renhao Lu, Anna M. Kolarzyk, W. Daniel Stamer, Esak Lee
{"title":"Human ocular fluid outflow on-chip reveals trabecular meshwork-mediated Schlemm’s canal endothelial dysfunction in steroid-induced glaucoma","authors":"Renhao Lu, Anna M. Kolarzyk, W. Daniel Stamer, Esak Lee","doi":"10.1038/s44161-025-00704-3","DOIUrl":"10.1038/s44161-025-00704-3","url":null,"abstract":"Glaucoma is a leading cause of blindness, featuring elevated intraocular pressure and consequential optic nerve damage1. While elevated intraocular pressure is due to impaired ocular fluid outflow through both the trabecular meshwork (TM) and the lymphatic-like Schlemm’s canal (SC) endothelium, the mechanism by which SC endothelium regulates fluid outflow in cooperation with the TM in healthy and glaucomatous conditions remains unclear. Here we create a human ocular fluid outflow on-chip, composed of a three-dimensional lymphatic or SC endothelium surrounded by TM and draining interstitial fluid. Using the system, we recapitulate steroid-induced glaucoma, characterized by decreased fluid outflow and tightened SC endothelial junctions. We further reveal that the glaucoma phenotypes are induced by an ALK5/VEGFC-mediated SC endothelial dysfunction in the presence of TM. The ocular fluid outflow on-chip provides a unique platform for bridging traditional in vitro and in vivo models of ocular lymphatic physiology and disease. Lu et al. created a human ocular outflow on-chip, composed of 3D Schlemm’s canal endothelium surrounded by trabecular meshwork and draining interstitial fluid, revealing ALK5/VEGFC signaling as a therapeutic target for steroid-induced glaucoma.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1066-1076"},"PeriodicalIF":10.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12443618/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Glaucoma discovery on a chip","authors":"Naoki Kiyota, Susan E. Quaggin","doi":"10.1038/s44161-025-00694-2","DOIUrl":"10.1038/s44161-025-00694-2","url":null,"abstract":"Increased intraocular pressure due to decreased outflow of aqueous humor from the anterior chamber of the eye is a major risk factor for the development of glaucoma, a leading cause of blindness. A new bioengineered device models ocular fluid outflow on a chip to advance discovery in the pathogenesis and treatment of glaucoma.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1038-1039"},"PeriodicalIF":10.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alireza P. Shabanzadeh, Dene Ringuette, Michal Syonov, Qisi Wu, Nardos G. Tassew, Eric K. Mun, Autumn Meek, Starlee Lively, Samuel E. Suntharalingham, Mia Mojica, Leonardo Olijnyk, Beiping Qiang, Warren D. Foltz, Mark Reed, Ignace Moya, Carla Brown, Jinzhou Feng, Xinyue Qin, Pavan Sudheer Akula, Thomas Wälchli, Peter L. Carlen, Paula Alcaide-Leon, Philippe P. Monnier
{"title":"Inhibition of proprotein convertase SKI-1 prevents blood vessel alteration after stroke","authors":"Alireza P. Shabanzadeh, Dene Ringuette, Michal Syonov, Qisi Wu, Nardos G. Tassew, Eric K. Mun, Autumn Meek, Starlee Lively, Samuel E. Suntharalingham, Mia Mojica, Leonardo Olijnyk, Beiping Qiang, Warren D. Foltz, Mark Reed, Ignace Moya, Carla Brown, Jinzhou Feng, Xinyue Qin, Pavan Sudheer Akula, Thomas Wälchli, Peter L. Carlen, Paula Alcaide-Leon, Philippe P. Monnier","doi":"10.1038/s44161-025-00691-5","DOIUrl":"10.1038/s44161-025-00691-5","url":null,"abstract":"Neutralizing factors involved in blood vessel dysfunction offer a promising strategy for stroke recovery. Many extracellular proteins need enzymatic activation to function, and blocking this activation is an untapped approach to restoring vessel integrity. Here we demonstrate that inhibition of the extracellular protease SKI-1 with PF-429242 restores blood vessel integrity and promotes functional recovery in both large and small animal models for stroke. Single-cell mRNA sequencing identified molecular signatures suggesting that PF-429242 restores the expression of genes involved in vessel integrity in endothelial cells. Moreover, we identify a mechanism whereby RGMa cleavage by SKI-1 is required for RGMa to interact with Neogenin and alter vessel integrity. Either preventing RGMa cleavage or deleting Neogenin on endothelial cells reduced blood vessel dysfunction, increased tissue preservation and restored brain function after stroke. This work identifies a much-needed therapeutic strategy that restores blood vessel integrity and functionality, showing efficacy in large and small animals. Shabanzadeh et al. identify and validate a pathway whereby RGMa cleavage by SKI-1 modifies gene expression related to blood–brain barrier (BBB) integrity after stroke. SKI-1 inhibition restores BBB integrity and neuronal function in mouse and rabbit stroke models.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1094-1113"},"PeriodicalIF":10.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathryn Berg, Joshua Gorham, Faith Lundt, Jonathan Seidman, Martina Brueckner
{"title":"Endocardial primary cilia and blood flow regulate EndoMT during endocardial cushion development","authors":"Kathryn Berg, Joshua Gorham, Faith Lundt, Jonathan Seidman, Martina Brueckner","doi":"10.1038/s44161-025-00697-z","DOIUrl":"10.1038/s44161-025-00697-z","url":null,"abstract":"Valvular heart disease affects 2.5% of the population and is frequently associated with congenital heart disease. Blood flow is critical for valve formation, but the cellular mechanosensors translating flow into the transcriptional regulation of valve development remain undiscovered. Here, we identify that primary cilia and blood flow in mouse embryos regulate early valve development in vivo by regionally controlling endothelial-to-mesenchymal transition (EndoMT) through the modulation of Krüppel-like factor 4 (Klf4) in the endocardial cushions. Endocardial ciliation decreases during cushion development in regions of high shear stress, correlating with KLF4 downregulation and EndoMT progression. Mouse embryos lacking cilia exhibit blood flow-dependent accumulation of KLF4 and impaired cushion cellularization. Single-nucleus RNA sequencing revealed that the cilia-knockout and contractility-knockout endocardium fails to progress through EndoMT pseudostages, retains endothelial markers, and has reduced EndoMT and mesenchymal genes that KLF4 antagonizes. These data indicate that endocardial primary cilia function as mechanosensors in cushion development through the regional regulation of KLF4. Berg et al. identify that primary cilia regulate early valve development in mouse embryos by participating in cushion development, where they function as mechanosensors regulating endothelial-to-mesenchymal transition through the modulation of Klf4.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1114-1134"},"PeriodicalIF":10.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Blocking SKI-1 to rescue the blood–brain barrier and improve stroke recovery","authors":"Ken Arai, Masafumi Ihara","doi":"10.1038/s44161-025-00683-5","DOIUrl":"10.1038/s44161-025-00683-5","url":null,"abstract":"The blood–brain barrier is an important therapeutic target in the development of drugs to treat stroke. A recent study finds that inhibiting SKI-1 protects blood–brain barrier integrity and improves neurological recovery in mouse and rabbit models of stroke.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1040-1042"},"PeriodicalIF":10.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Bridging the inflammation gap by IL-6 inhibition","authors":"Michael D. Shapiro","doi":"10.1038/s44161-025-00702-5","DOIUrl":"10.1038/s44161-025-00702-5","url":null,"abstract":"Targeting inflammation has emerged as a promising strategy to reduce residual cardiovascular risk. A study now uses human genetics to show that IL-6 inhibition is associated with a lower risk of cardiovascular disease with no increase in infection, supporting the use of pharmacological treatments that target IL-6 rather than its receptor.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1043-1044"},"PeriodicalIF":10.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lanyue Zhang, Murad Omarov, Lingling Xu, Emil deGoma, Pradeep Natarajan, Marios K. Georgakis
{"title":"IL6 genetic perturbation mimicking IL-6 inhibition is associated with lower cardiometabolic risk","authors":"Lanyue Zhang, Murad Omarov, Lingling Xu, Emil deGoma, Pradeep Natarajan, Marios K. Georgakis","doi":"10.1038/s44161-025-00700-7","DOIUrl":"10.1038/s44161-025-00700-7","url":null,"abstract":"Human genetics supports a causal involvement of IL-6 signaling in atherosclerotic cardiovascular disease, prompting the clinical development of anti-IL-6 therapies. Genetic evidence has historically focused on IL6R missense variants, but emerging cardiovascular treatments target IL-6, not its receptor, questioning the translatability of genetic findings. Here we develop a genetic instrument for IL-6 signaling downregulation comprising IL6 locus variants that mimic the effects of the anti-IL-6 antibody ziltivekimab and use it to predict the effects of IL-6 inhibition on cardiometabolic and safety endpoints. Similar to IL6R, we found that genetically downregulated IL-6 signaling via IL6 perturbation is associated with lower lifetime risks of coronary artery disease, peripheral artery disease and ischemic atherosclerotic stroke in individuals of European and East Asian ancestry. Unlike IL6R missense variants linked to bacterial infections, the IL6 instrument was associated with lower risk of pneumonia hospitalization. Our data suggest that IL-6 inhibition can reduce cardiovascular risk without major unexpected safety concerns. Zhang et al. show that genetically simulated IL-6 inhibition is associated with a reduced risk of cardiovascular disease and no increase in infection risk, supporting the use of emerging pharmacological treatments targeting IL-6 rather than its receptor.","PeriodicalId":74245,"journal":{"name":"Nature cardiovascular research","volume":"4 9","pages":"1172-1186"},"PeriodicalIF":10.8,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12436178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144981655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}