Circulation research最新文献

{"title":"Dysregulated Protein s-Nitrosylation Promotes Nitrosative Stress and Disease Progression in Heart Failure With Preserved Ejection Fraction.","authors":"Zhen Li,Kyle B LaPenna,Natalie D Gehred,Xiaoman Yu,W H Wilson Tang,Jake E Doiron,Huijing Xia,Jingshu Chen,Ian H Driver,Frank B Sachse,Naoto Muraoka,Antonia Katsouda,Paraskevas Zampas,Amelia G Haydel,Heather Quiriarte,Timothy D Allerton,Alexia Zagouras,Jennifer Wilcox,Tatiana Gromova,Yueqin Zheng,Andreas Papapetropoulos,Sanjiv J Shah,Traci T Goodchild,Martin B Jensen,Thomas E Sharp,Thomas M Vondriska,David J Lefer","doi":"10.1161/circresaha.124.326042","DOIUrl":"https://doi.org/10.1161/circresaha.124.326042","url":null,"abstract":"BACKGROUNDRecent studies suggest aberrant elevation of iNOS (inducible NO synthase) expression and excessive protein s-nitrosylation promote the pathogenesis of heart failure with preserved ejection fraction (HFpEF). However, the interplay between NO bioavailability, enzymatic regulation of protein s-nitrosylation by transnitrosylase and denitrosylase, and HFpEF progression remains poorly defined. We investigated the molecular basis of nitrosative stress in HFpEF, focusing on alterations in NO signaling and regulation of protein s-nitrosylation.METHODSCirculating nitrite (NO bioavailability) and nitrosothiols were quantified in patients with HFpEF. Parallel studies using rodent models of cardiometabolic HFpEF were performed to evaluate cardiac function, NO signaling, and total nitroso species during disease progression. Single-nucleus RNA sequencing and proteomic analysis were conducted to identify regulatory genes and cellular targets of pathological s-nitrosylation.RESULTSIn patients with HFpEF, circulating nitrosothiols were significantly elevated, indicating heightened nitrosative stress, whereas nitrite levels remained unchanged. In Zucker fatty obese rats, NO bioavailability declined with age, whereas total nitroso species progressively increased as HFpEF worsened. Transcriptomic analysis revealed marked upregulation of a transnitrosylase HBb (hemoglobin-β subunit), validated in both rat and human HFpEF hearts. Enzymatic assays demonstrated aberrant functions of Trx2 (thioredoxin 2) and GSNOR (S-nitrosoglutathione reductase) in Zucker fatty hearts. Cell-based experiments confirmed that altered expression or function of HBb, Trx2, and GSNOR resulted in elevated cellular RxNO. Additionally, similar dysregulation of s-nitrosylation dynamics was observed in the peripheral organs, such as the kidneys and livers, in HFpEF.CONCLUSIONSThese data demonstrate that nitrosative stress, evidenced by dysregulated protein s-nitrosylation occurs in the heart and peripheral organs in cardiometabolic HFpEF. Pathological alterations in NO bioavailability resulting from alterations in NOS expression or function alone do not account for this phenotype. Instead, pathological protein s-nitrosylation results in part from the imbalance between transnitrosylase and denitrosylase function. Restoration of physiological levels of protein s-nitrosylation and NO signaling may represent an effective therapeutic target for HFpEF.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"38 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071733","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":"Circular RNA Cdr1as Modulates Macrophage-Mediated Cardiac Reparative Function.","authors":"Carolina Gonzalez,Maria Cimini,Vandana Mallaredy,Cindy Benedict,Darukeshwara Joladarashi,Charan Thej,Zhongjian Cheng,May Trungcao,Amit Kumar Rai,Venkata Naga Srikanth Garikipati,Raj Kishore","doi":"10.1161/circresaha.125.326377","DOIUrl":"https://doi.org/10.1161/circresaha.125.326377","url":null,"abstract":"BACKGROUNDMechanisms of macrophage switching from proinflammatory to anti-inflammatory phenotypes are not well understood. Circular RNAs, a new class of noncoding RNAs, are implicated in immune modulation. We recently identified circ-cdr1as as a regulator of macrophage phenotype in bone marrow-derived macrophages; however, its role in immunomodulation during cardiovascular injury remains unknown.METHODSCell-specific expression levels of circ-cdr1as were determined in the mouse hearts postmyocardial infarction. Circ-cdr1as was overexpressed in fluorescently labeled bone marrow-derived macrophages and injected into the ischemic myocardium immediately following myocardial infarction. The effect of AAV9 (adeno-associated virus-serotype 9)-mediated systemic delivery of circ-Cdr1as on postmyocardial infarction cardiac function and structure was determined. Downstream mechanisms were studied using gain and loss-of-function strategies.RESULTSCardiac cell-specific expression analysis showed significant downregulation of circ-cdr1as only in macrophages and cardiomyocytes. Overexpression of circ-cdr1as in bone marrow-derived macrophages, injected into the ischemic myocardium, retained their anti-inflammatory phenotype and significantly improved left ventricular functions and reduced infarct size. Systemic delivery of AAV9-circ-cdr1as showed similar cardiac reparative activity. Mechanistically, circ-cdr1as directly binds and sponges microRNA-7 and increases the expression of target KLF4 (Kruppel-like factor 4). Loss and gain of function studies show that modulation of microRNA 7 and KLF recapitulates macrophage phenotypic changes.CONCLUSIONSCirc-cdr1as plays a crucial role in regulating the anti-inflammatory phenotype of macrophages through modulation of microRNA 7 and its target gene KLF4. Therefore, circ-cdr1as holds potential as an anti-inflammatory regulator in tissue inflammation postcardiac injury.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"46 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068358","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":"Macrophage-Derived CCL24 Promotes Cardiac Fibrosis Via Fibroblast CCR3.","authors":"Preethy Parthiban,Fanta Barrow,Haiguang Wang,Upendra Chalise,Natalia Araujo,Fernando Souza-Neto,Huy Nguyen,Micah Draxler,Jean Pierre Pallais,Dogacan Yucel,Hong Liu,Erin Ciske,Patrick Fehrenbach,Andrew Hakeem,Sang Hun Lee,Adam Herman,Marc E Rothenberg,Samuel Dudley,Jop H van Berlo,Xavier S Revelo","doi":"10.1161/circresaha.125.326599","DOIUrl":"https://doi.org/10.1161/circresaha.125.326599","url":null,"abstract":"BACKGROUNDInflammation is a significant risk factor and contributor to the development of cardiovascular disease by driving both adaptive and maladaptive responses to cardiac injury. Macrophages are the most abundant immune cells in the heart and play an important role in the remodeling of cardiac tissue. Cardiac resident macrophages are integral components of the myocardium, where they have key roles in the response to inflammation, tissue injury, and remodeling. However, the precise mechanisms by which cardiac resident macrophages regulate remodeling in heart failure remain poorly understood.METHODS AND RESULTSWe have identified a subpopulation of cardiac resident macrophages that expresses high levels of the CCL24 (C-C motif chemokine ligand 24) during pressure overload-induced injury. Following transverse aortic constriction, CCL24 deficiency ameliorated cardiac fibrosis, suggesting a pathological role for CCL24 and revealing that cardiac resident macrophages are a heterogeneous population with dichotomous roles in mediating cardiac remodeling. Mechanistically, CCL24 directly activated cardiac fibroblasts through its sole receptor, CCR3 (C-C chemokine receptor type 3), in an inflammation-independent process. The engagement of the CCR3 receptor promoted fibroblast proliferation and activation via PI3K-induced Akt phosphorylation and the release of the key fibrotic cytokine TGF (transforming growth factor) β. To determine the in vivo role of CCR3 in fibroblast activation during cardiac remodeling, we used CRISPR/Cas9 to generate fibroblast-specific CCR3-deficient mice. Following pressure overload, fibroblast-specific deletion of CCR3 improved cardiac function and reduced fibrosis to a degree comparable to that observed in CCL24-deficient mice. Notably, administration of a CCL24-blocking antibody or a CCR3 antagonist enhanced cardiac function in pressure-overloaded mice, underscoring the CCL24-CCR3 axis as a promising therapeutic target for heart failure.CONCLUSIONSMacrophage-derived CCL24 aggravates fibrosis via the CCR3 receptor, impairing cardiac function in heart failure.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"65 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068357","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":"SPOP Is a Key Trigger of Pathological Cardiac Hypertrophy and Heart Failure.","authors":"Hao Wu,Yuting Zhuang,Ying Yue,Jiangqi Liu,Jin Han,Yiming Yao,Xi Xu,Junwu Liu,Yuyang Li,Zhenbo Yang,Yizheng Wang,Qiwen Ning,Wei Yuan,Bo Meng,Xiaoxi Hu,Zhongrui Tian,Ying Yang,Jialiang Li,Yang Zhang,Baofeng Yang,Zhenwei Pan,Yanjie Lu","doi":"10.1161/circresaha.125.326129","DOIUrl":"https://doi.org/10.1161/circresaha.125.326129","url":null,"abstract":"BACKGROUNDDisturbance in protein synthesis and degradation plays a crucial role in various biological and pathological processes. E3 ubiquitin ligase substrate-binding adaptor SPOP (speckle-type POZ protein) is substantially involved in cancer progression. The study aims to investigate the biological function of SPOP in cardiac hypertrophy and heart failure.METHODSWe generated cardiac-specific transgenic and knockout mice to evaluate the functional role of SPOP in transverse aortic constriction-induced cardiac hypertrophy and heart failure. RNA-sequencing, proteomics, and protein mass spectrometry analysis, and multiple molecular biological methodologies were employed to investigate its function and mechanisms in cardiac hypertrophic mice.RESULTSSPOP was significantly upregulated in human heart failure, hypertrophic mouse hearts, and Ang II (angiotensin II)-treated neonatal mouse ventricular cardiomyocytes. SPOP induced the expression of hypertrophic markers ANP (atrial natriuretic peptide), BNP (B-type natriuretic peptide), and β-MHC (β-myosin heavy chain), increased cardiomyocyte size, whereas SPOP deficiency exhibited the opposite effects in hypertrophic neonatal mouse ventricular cardiomyocytes. Furthermore, cardiac-specific overexpression of SPOP led to cardiac hypertrophy and heart failure in mice. In contrast, cardiac-specific knockout of SPOP markedly attenuated transverse aortic constriction-induced cardiac hypertrophy and improved heart failure. In parallel, SPOP presented prohypertrophic effects, and SPOP loss-of-function substantially rescued Ang II-induced hypertrophic phenotype in neonatal mouse ventricular cardiomyocytes. Mechanistically, SPOP is transcriptionally activated by p300 under cardiac hypertrophy, subsequently interacting with and promoting ubiquitination-mediated degradation of TFEB (transcription factor EB) independently of its phosphorylation status, a key regulator for transcription of lysosomal biogenesis and autophagy-related genes, leading to blockage of autophagy and mitophagy, which eventually causes cardiac hypertrophy and heart failure. Overexpression of TFEB rescued SPOP-induced these alterations. Noticeably, a specific inhibitor of SPOP was able to prevent the development of cardiac hypertrophy and heart failure.CONCLUSIONSSPOP is a detrimental factor in pathological cardiac hypertrophy via promoting ubiquitination-induced degradation of TFEB, a critical regulator of the autophagy-lysosomal pathway. Targeting SPOP represents a promising therapeutic strategy for hypertrophy-related heart failure.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"52 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059162","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":"Targeting Cardiomyocyte PCNA and POLD1 Prevents Pathological Myocardial Hypertrophy.","authors":"Soumojit Pal,Michael S Glennon,Benjamin R Nixon,Ethan J Chetkof,Puneeth Shridhar,Chintha M Kathiresan,Morgan B Glasser,Christina J Waldron,Lanping Guo,Nicolas G Clavere,Dipanjan Banerjee,Jenny H Kim,Jason R Becker","doi":"10.1161/circresaha.124.325647","DOIUrl":"https://doi.org/10.1161/circresaha.124.325647","url":null,"abstract":"BACKGROUNDActivation of cell cycle regulatory pathways has been detected during pathological cardiomyocyte growth. However, it has remained unclear whether DNA synthesis pathways play a direct role in cardiomyocyte hypertrophy. We previously discovered in a mouse model of hypertrophic cardiomyopathy that there was increased DNA synthesis, which led to cardiomyocyte endoreplication and replication stress-induced DNA damage. We hypothesized that targeting cardiomyocyte endoreplication pathways could reduce pathological myocardial hypertrophy.METHODSWe utilized murine models of hypertrophic cardiomyopathy secondary to mutations in cardiac Mybpc3 (myosin-binding protein C3)-/- or Myh6 (myosin heavy chain 6)R404Q and transverse aortic constriction as a model of pressure overload cardiomyocyte hypertrophy. We manipulated in vivo p21 protein levels using transgenic mouse models or viral transduction. Cardiomyocyte endoreplication was assessed using flow cytometry and immunohistochemistry of cardiomyocyte nuclei. We also utilized proteomics, proximity ligation assays, and human-induced pluripotent stem cell-derived cardiomyocytes.RESULTSWe discovered that p21 protein peaked during the early stages of hypertrophic growth in both murine hypertrophic cardiomyopathy models and a pressure overload hypertrophy model. Using genetic manipulation of p21 expression, we discovered that cardiomyocyte endoreplication and hypertrophic growth were negatively correlated with p21 expression. Mechanistically, we discovered that p21 bound to PCNA (proliferating cell nuclear antigen), which led to a reduction of PCNA binding to POLD1 (DNA polymerase delta 1). Directly targeting PCNA or POLD1 prevented cardiomyocyte DNA synthesis and hypertrophic cardiomyocyte growth. Cardiomyocyte-selective overexpression of p21 using an adeno-associated virus vector reduced long-term pathological left ventricular hypertrophy and improved diastolic function in a preclinical murine model of hypertrophic cardiomyopathy (Myh6R404Q).CONCLUSIONSOur results demonstrate that PCNA-POLD1-mediated cardiomyocyte endoreplication drives hypertrophic cardiomyocyte growth, and p21 serves as a negative regulator of this process. Targeting these pathways demonstrates therapeutic potential in preventing pathological myocardial hypertrophy.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"130 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059036","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":"Functional Analysis of a Homozygous MYBPC3 Null Allele in Human Pediatric Patients.","authors":"Jeffrey S Bennett,Patrick T Wood,Katherine L Dominic,Christine S Moravec,Kenneth S Campbell,Julian E Stelzer","doi":"10.1161/circresaha.125.326637","DOIUrl":"https://doi.org/10.1161/circresaha.125.326637","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"87 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059088","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":"Single-Nucleus RNAseq Defines Cellular and Molecular Landscape of Dysfunctional Right Atrium in Pulmonary Artery Banded Swine.","authors":"Jenna B Mendelson,Jacob D Sternbach,Minwoo Kim,Ryan A Moon,Jeffrey C Blake,Rashmi M Raveendran,Lynn M Hartweck,Walt Tollison,Matthew Lahiri,John P Carney,Felipe Kazmirczak,Gaurav Choudhary,Kurt W Prins","doi":"10.1161/circresaha.125.326892","DOIUrl":"https://doi.org/10.1161/circresaha.125.326892","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"15 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059037","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":"Lkb1 Downregulation Links PVAT Remodeling to Aortic Dilation or Aneurysm.","authors":"Zhaohua Cai, Min Liang, Yangjing Jiang, Haiping Chen, Yunwen Hu, Yijie Huang, Huanhuan Huo, Linghong Shen, Ben He","doi":"10.1161/CIRCRESAHA.125.326297","DOIUrl":"10.1161/CIRCRESAHA.125.326297","url":null,"abstract":"<p><strong>Background: </strong>Perivascular adipose tissue (PVAT) is a unique adipose tissue depot that surrounds the blood vessels throughout the body. PVAT regulates vascular physiological homeostasis and contributes to the pathogenesis of vascular diseases. Lkb1 (liver kinase b1) is strongly associated with the development of cancer and cardiovascular diseases.</p><p><strong>Methods: </strong>In this study, we generated tamoxifen-inducible <i>Lkb1</i>^{<i>flox/flox</i>}<i>;Pdgfrα-Cre</i>^<i>ERT2</i>, <i>Lkb1</i>^{<i>flox/flox</i>};<i>Pdgfrβ-Cre</i>^<i>ERT2</i>, and <i>Lkb1</i>^{<i>flox/flox</i>};<i>Myh11-Cre</i>^<i>ERT2</i> mice to investigate the role of Lkb1 in PVAT and related vessel function.</p><p><strong>Results: </strong>We found that Lkb1 is a PVAT-enriched gene that is strikingly downregulated during Ang II (angiotensin II)-induced aortic aneurysm formation. Lkb1 deficiency in Pdgfrα⁺ fibroblast induces PVAT dysfunction, which in turn results in gradual aortic dilation and exaggerates Ang II-induced aortic aneurysm formation in mice. In addition, Lkb1 deficiency in Myh11⁺ (smooth muscle myosin heavy chain 11) or Pdgfrβ⁺ (platelet-derived growth factor receptor beta) mural cells leads to PVAT dysfunction and spontaneous aortic dilation or aneurysm formation. Mechanistically, genetic deletion of Lkb1 activates renin-angiotensin system in PVAT, which drives vascular smooth muscle cell phenotype switching via paracrine signaling. Most importantly, treatment with either renin inhibitor aliskiren or Ang II receptor blocker valsartan rescues vascular smooth muscle cell phenotypic switching and aortic dilation in <i>Lkb1</i>^{<i>flox/flox</i>};<i>Pdgfrα-Cre</i>^<i>ERT2</i> mice.</p><p><strong>Conclusions: </strong>Our work strongly suggests that Lkb1 deficiency in PVAT drives vascular smooth muscle cell phenotypic switching and aortic dilation and aneurysm formation. Lkb1, via its regulation of renin-angiotensin system in PVAT, maintains vessel homeostasis.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1006-1023"},"PeriodicalIF":16.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944814","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":"GUCY1A1-LDHA Axis Suppresses Ferroptosis in Cardiac Ischemia-Reperfusion Injury.","authors":"Ming Yin, Su Li, Muyin Liu, Wentao Zhu, Yuqiong Chen, Wenyan Qiu, Qiyu Li, Youran Li, Jinxiang Chen, You Zhou, Danbo Lu, Chenguang Li, Zhangwei Chen, Juying Qian, Junbo Ge","doi":"10.1161/CIRCRESAHA.124.326029","DOIUrl":"10.1161/CIRCRESAHA.124.326029","url":null,"abstract":"<p><strong>Background: </strong>Ischemia-reperfusion injury compromises revascularization strategies for myocardial infarction and contributes to cardiac microvascular disorders. This study aimed to investigate the role of the sGC (soluble guanylate cyclase)-cGMP (cyclic guanosine monophosphate)-PKG (protein kinase G) pathway in cardiac microvascular reperfusion injury with a focus on ferroptosis.</p><p><strong>Methods: </strong>Key genes in the sGC-cGMP-PKG pathway were analyzed at different reperfusion times using bulk and single-cell mRNA sequencing. Endothelial cell (EC) specific conditional GUCY1A1 (guanylate cyclase soluble subunit alpha 1) knockout mice (GUCY1A1^flox/flox/-CreERT2) and adeno-associated virus transfer-induced EC-specific GUCY1A1-overexpressing mice were assessed for cardiac microvascular reperfusion injury. LDHA (lactate dehydrogenase A) and GPX4 (glutathione peroxidase 4) phosphorylation sites were identified by mass spectrometry and mutationally inactivated via the CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and their associated protein 9) system. Protein interactions and chaperone-mediated autophagy of GPX4 were detected using coimmunoprecipitation assays.</p><p><strong>Results: </strong>GUCY1A1 was decreased in the EC group after cardiac ischemia-reperfusion injury. EC-specific knockout of GUCY1A1 further reduced microvascular perfusion, increased the no-reflow area, and enlarged the infarction area in the acute phase of ischemia-reperfusion injury, ultimately aggravating cardiac dysfunction and structural remodeling in the chronic phase. In contrast, GUCY1A1 overexpression or its activator, vericiguat, alleviated microvascular dysfunction via the suppression of endothelial ferroptosis; the effects were majorly dependent on PKG activity. Mechanistically, PKG phosphorylated LDHA at threonine 95 and activated the LDHA moonlighting kinase function to phosphorylate GPX4, resulting in reduced chaperone-mediated autophagy-dependent degradation of GPX4 and ferroptosis. In human ischemic cardiomyopathy, GUCY1A1 expression, LDHA phosphorylation at threonine 95, and GPX4 phosphorylation at serine 131 were negatively associated with lipid peroxidation and cardiac fibrosis, suggesting that this pathway was involved in the pathogenesis of cardiac ischemia-reperfusion injury.</p><p><strong>Conclusions: </strong>These findings indicate that the compromise of the sGC-cGMP-PKG pathway is associated with reduced phosphorylation of LDHA and GPX4, and that GUCY1A1 activation may be considered as a strategy to alleviate endothelial ferroptosis and cardiac microvascular reperfusion injury.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"986-1005"},"PeriodicalIF":16.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944405","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":"Endurance Training Enhances Sex-Specific Cardioprotective Metabolism.","authors":"Pauline Brochet, Samuel Montalvo, Maléne E Lindholm, David Jimenez-Morales, Christopher A Jin, Blake B Rasmussen, William E Kraus, Zhen Yan, Matthew T Wheeler, Daniel H Katz","doi":"10.1161/CIRCRESAHA.125.326494","DOIUrl":"10.1161/CIRCRESAHA.125.326494","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"1045-1047"},"PeriodicalIF":16.2,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944416","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}