Circulation research最新文献

{"title":"NEDD4-Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction.","authors":"Xin Tang, Xiameng Liu, Xinqi Sha, Yan Zhang, Yan Zu, Qiyao Fan, Lulu Hu, Shixiu Sun, Zhiren Zhang, Feng Chen, ChengHui Yan, Xin Chen, Yueyue Xu, Wen Chen, Yongfeng Shao, Jiaxi Gu, Jun Pu, Bo Yu, Yaling Han, Liping Xie, Yi Han, Yong Ji","doi":"10.1161/CIRCRESAHA.124.324872","DOIUrl":"10.1161/CIRCRESAHA.124.324872","url":null,"abstract":"<p><strong>Background: </strong>The decrease in S-nitrosoglutathione reductase (GSNOR) leads to an elevation of S-nitrosylation, thereby exacerbating the progression of cardiomyopathy in response to hemodynamic stress. However, the mechanisms under GSNOR decrease remain unclear. Here, we identify NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) as a novel molecule that plays a crucial role in the pathogenesis of pressure overload-induced cardiac hypertrophy, by modulating GSNOR levels, thereby demonstrating significant therapeutic potential.</p><p><strong>Methods: </strong>Protein synthesis and degradation inhibitors were used to verify the reasons for the decrease in GSNOR. Mass spectrometry and database filtering were used to uncover NEDD4, the E3 Ub (ubiquitin) ligase, involved in GSNOR decrease. NEDD4 cardiomyocyte-specific deficiency mice were used to evaluate the role of NEDD4 and NEDD4-induced ubiquitination of GSNOR in cardiac hypertrophy in vivo. Both IBM (indolebutenate methyl ester derivatives), a highly specific NEDD4 inhibitor, and indole-3-carbinol, a NEDD4 inhibitor currently undergoing phase 2 clinical trial, were used to effectively suppress the NEDD4/GSNOR axis.</p><p><strong>Results: </strong>GSNOR protein levels were reduced, while mRNA levels remained unchanged in myocardium samples from hypertrophic patients and transverse aortic constriction-induced mice, indicating GSNOR is regulated by ubiquitination. NEDD4, an E3 Ub ligase, was associated with GSNOR ubiquitination, which exhibited significantly higher expression levels in hypertrophic myocardial samples. Moreover, either the NEDD4 enzyme-dead mutant or GSNOR nonubiquitylated mutant decreased GSNOR ubiquitination and inhibited cardiac hypertrophic growth. Cardiomyocyte-specific NEDD4 deficiency inhibited cardiac hypertrophy in vitro and in vivo. NEDD4 inhibitor IBM effectively suppressed GSNOR ubiquitination and cardiac hypertrophy. Clinically, indole-3-carbinol, a NEDD4 inhibitor in phase II clinical trials used as an antitumor drug, demonstrated comparable efficacy.</p><p><strong>Conclusions: </strong>Our findings showed that upregulated NEDD4 leads to GSNOR ubiquitination and subsequent degradation, thereby facilitating the progression of cardiac hypertrophy. NEDD4 inhibitors may serve as a potential therapeutic strategy for the treatment of cardiac hypertrophy and heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"422-438"},"PeriodicalIF":16.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022453","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":"Mineral Stress Drives Loss of Heterochromatin: An Early Harbinger of Vascular Inflammaging and Calcification.","authors":"Chin Yee Ho, Meng-Ying Wu, Jirapath Thammaphet, Sadia Ahmad, James Ho C S, Lilia Draganova, Grace Anderson, Umesh S Jonnalagadda, Robert Hayward, Rukshana Shroff, Wilson Tan Lek Wen, Anja Verhulst, Roger Sy Foo, Catherine M Shanahan","doi":"10.1161/CIRCRESAHA.124.325374","DOIUrl":"10.1161/CIRCRESAHA.124.325374","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification is a detrimental aging pathology markedly accelerated in patients with chronic kidney disease. PLA (prelamin A) is a biomarker of vascular smooth muscle cell aging that accelerates calcification however the mechanisms remain undefined.</p><p><strong>Methods: </strong>Vascular smooth muscle cells were transduced with PLA using an adenoviral vector and epigenetic modifications were monitored using immunofluorescence and targeted polymerase chain reaction array. Epigenetic findings were verified in vivo using immunohistochemistry in human vessels, in a mouse model of inducible prelamin A expression, and in a rat model of chronic kidney disease-induced calcification. Transcriptomic and chromatin immunoprecipitation followed by sequencing analyses were used to identify gene targets impacted by changes in the epigenetic landscape. Molecular tools and antibody arrays were used to monitor the effects of mineral dysregulation on heterochromatin, inflammation, aging, and calcification.</p><p><strong>Results: </strong>Here, we report that depletion of the repressive heterochromatin marks, H3K9me3 (histone H3, lysine 9, trimethylation) and H3K27me3 (histone H3, lysine 27,trimethylation), is an early hallmark of vascular aging induced by both nuclear lamina dysfunction and dysregulated mineral metabolism, which act to modulate the expression of key epigenetic writers and erasers. Global analysis of H3K9me3 and H3K27me3 marks and pathway analysis revealed deregulation of insulin signaling and autophagy pathways as well as cross-talking DNA damage and NF-κB (nuclear factor κB) inflammatory pathways consistent with early activation of the senescence-associated secretory phenotype. Expression of PLA in vivo induced loss of heterochromatin and promoted inflammation and osteogenic differentiation which preceded aging indices, such as DNA damage and senescence. Vessels from children on dialysis and rats with chronic kidney disease showed prelamin A accumulation and accelerated loss of heterochromatin before the onset of calcification.</p><p><strong>Conclusions: </strong>Dysregulated mineral metabolism drives changes in the epigenetic landscape and nuclear lamina dysfunction that together promote early induction of inflammaging pathways priming the vasculature for downstream pathological change.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"379-399"},"PeriodicalIF":16.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fiber, Fatty Acids, and Blood Pressure: A Gut-Level Solution.","authors":"Mohd Mabood Khan, Annet Kirabo","doi":"10.1161/CIRCRESAHA.125.326065","DOIUrl":"10.1161/CIRCRESAHA.125.326065","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 4","pages":"358-360"},"PeriodicalIF":16.5,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arterial NALCN Knockdown Ameliorates Mineralocorticoid-Induced Hypertension and Arterial Overcontractility.","authors":"Hyeryeong Lee, Solah Park, Dong Jun Sung, Jin Ryeol An, Mi Seon Seo, Hyun Ju Noh, Jueng Soo You, Sung Hea Kim, Hana Cho, Bokyung Kim, Sang Woong Park, Young Min Bae","doi":"10.1161/CIRCRESAHA.124.325058","DOIUrl":"10.1161/CIRCRESAHA.124.325058","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"321-324"},"PeriodicalIF":16.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"X-Chromosome-Linked miRNAs Regulate Sex Differences in Cardiac Physiology.","authors":"James I Emerson, Wei Shi, Jose Paredes-Larios, William G Walker, Josiah E Hutton, Ileana M Cristea, William F Marzluff, Frank L Conlon","doi":"10.1161/CIRCRESAHA.124.325447","DOIUrl":"10.1161/CIRCRESAHA.124.325447","url":null,"abstract":"<p><strong>Background: </strong>Males and females exhibit distinct anatomic and functional characteristics of the heart, predisposing them to specific disease states.</p><p><strong>Methods: </strong>We identified microRNAs (miRNAs/miR) with sex-differential expression in mouse hearts.</p><p><strong>Results: </strong>Four conserved miRNAs are present in a single locus on the X-chromosome and are expressed at higher levels in females than males. We show miRNA, miR-871, is responsible for decreased expression of the protein SRL (sarcalumenin) in females. SRL is involved in calcium signaling, and we show it contributes to differences in electrophysiology between males and females. miR-871 overexpression mimics the effects of the cardiac physiology of conditional cardiomyocyte-specific Srl-null mice. Inhibiting miR-871 with an antagomir in females shortened ventricular repolarization. The human orthologue of miR-871, miR-888, coevolved with the SRL 3' untranslated region and regulates human SRL.</p><p><strong>Conclusions: </strong>These data highlight the importance of sex-differential miRNA mechanisms in mediating sex-specific functions and their potential relevance to human cardiac diseases.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"258-275"},"PeriodicalIF":16.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collagen Pyridinoline Cross-Links Are Absent in Reversible Myocardial Fibrosis.","authors":"Eman Akam-Baxter, Sterling J Ridley, Brianna F Moon, Peter Caravan, David E Sosnovik","doi":"10.1161/CIRCRESAHA.124.325406","DOIUrl":"10.1161/CIRCRESAHA.124.325406","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"315-317"},"PeriodicalIF":16.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000708","DOIUrl":"https://doi.org/10.1161/RES.0000000000000708","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 3","pages":"255-257"},"PeriodicalIF":16.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064083","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":"Bone Marrow Niche in Cardiometabolic Disease: Mechanisms and Therapeutic Potential.","authors":"Zachary A Kohutek, Heather L Caslin, Daniel J Fehrenbach, J Brett Heimlich, Jonathan D Brown, Meena S Madhur, P Brent Ferrell, Amanda C Doran","doi":"10.1161/CIRCRESAHA.124.323778","DOIUrl":"10.1161/CIRCRESAHA.124.323778","url":null,"abstract":"<p><p>Cardiovascular and cardiometabolic diseases are leading causes of morbidity and mortality worldwide, driven in part by chronic inflammation. Emerging research suggests that the bone marrow microenvironment, or marrow niche, plays a critical role in both immune system regulation and disease progression. The bone marrow niche is essential for maintaining hematopoietic stem cells (HSCs) and orchestrating hematopoiesis. Under normal conditions, this niche ensures a return to immune homeostasis after acute stress. However, in the setting of inflammatory conditions such as those seen in cardiometabolic diseases, it becomes dysregulated, leading to enhanced myelopoiesis and immune activation. This review explores the reciprocal relationship between the bone marrow niche and cardiometabolic diseases, highlighting how alterations in the niche contribute to disease development and progression. The niche regulates HSCs through complex interactions with stromal cells, endothelial cells, and signaling molecules. However, in the setting of chronic diseases such as hypertension, atherosclerosis, and diabetes, inflammatory signals disrupt the balance between HSC self-renewal and differentiation, promoting the excessive production of proinflammatory myeloid cells that exacerbate the disease. Key mechanisms discussed include the effects of hyperlipidemia, hyperglycemia, and sympathetic nervous system activation on HSC proliferation and differentiation. Furthermore, the review emphasizes the role of epigenetic modifications and metabolic reprogramming in creating trained immunity, a phenomenon whereby HSCs acquire long-term proinflammatory characteristics that sustain disease states. Finally, we explore therapeutic strategies aimed at targeting the bone marrow niche to mitigate chronic inflammation and its sequelae. Novel interventions that modulate hematopoiesis and restore niche homeostasis hold promise for the treatment of cardiometabolic diseases. By interrupting the vicious cycle of inflammation and marrow dysregulation, such therapies may offer new avenues for reducing cardiovascular risk and improving patient outcomes.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 3","pages":"325-353"},"PeriodicalIF":16.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vps4a Mediates a Unified Membrane Repair Machinery to Attenuate Ischemia/Reperfusion Injury.","authors":"Xiaozhi Huang, Jiayin Zhang, Chen Xu, Ranran Cao, Peijun Jiang, Xue Ji, Wenyi Wang, Zhishan Huang, Peidong Han","doi":"10.1161/CIRCRESAHA.124.325290","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325290","url":null,"abstract":"<p><strong>Background: </strong>Cardiac ischemia/reperfusion disrupts plasma membrane integrity and induces various types of programmed cell death. The ESCRT (endosomal sorting complex required for transport) proteins, particularly AAA-ATPase Vps4a (vacuolar protein sorting 4a), play an essential role in the surveillance of membrane integrity. However, the role of ESCRT proteins in the context of cardiac injury remains unclear.</p><p><strong>Methods: </strong>We simultaneously visualized the formation of membrane blebs and the subcellular translocation of Vps4a during a variety of cell death programs in primary cardiomyocytes. <i>Vps4a</i> cardiomyocyte-specific knockout and overexpression mice were generated and characterized. In vivo and ex vivo surgeries were performed to determine the effects of altered Vps4a expression levels on plasma membrane repair and cell survival. Given the role of Ripk3 (receptor-interacting kinase 3)-mediated pore formation in regulating cell membrane integrity, hearts from <i>Ripk3</i> and <i>Vps4a</i> double-knockout mice were examined. The sequential recruitment of upstream ESCRT components that promote the translocation of Vps4a to injured sites was also assessed using genetic gain- and loss-of-function approaches. Finally, we overexpressed a mutated form of Vps4a with defective ATPase activity and investigated its function during cardiomyocyte membrane repair.</p><p><strong>Results: </strong>Ischemia/reperfusion stimulation or forced induction of apoptosis, necroptosis, and pyroptosis in primary cardiomyocytes leads to membrane blebbing and the exposure of phosphatidylserine to the extracellular space. In response to injury, Vps4a promptly translocates to injured sites to reseal damaged membranes. <i>Vps4a</i> gain- and loss-of-function in the postnatal stage minimally affects cardiac structure formation and function. However, in the context of ischemia/reperfusion stimulation, overexpression of <i>Vps4a</i> protects cardiomyocytes against injury, whereas <i>Vps4a</i>-deficient hearts are more susceptible to cell damage. Additionally, <i>Ripk3</i> deletion abrogates the detrimental effects of <i>Vps4a</i> deficiency during ischemia/reperfusion injury, and the Ca²⁺-Alix-Ist1 axis plays an essential role in recruiting Vps4a to the injured site. Mechanistically, Vps4a promotes the shedding of plasma membrane blebs to restrict permeability to the extracellular environment, and the surveillance of membrane integrity requires the ATPase activity of Vps4a.</p><p><strong>Conclusions: </strong>These results demonstrate that Vps4a-mediated plasma membrane repair is an intrinsic cell protection machinery that antagonizes cardiac ischemia/reperfusion injury, and our findings may contribute to the development of therapeutic strategies towards attenuating cardiac injury.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 3","pages":"279-296"},"PeriodicalIF":16.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063994","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":"BRISC-Mediated PPM1B-K63 Deubiquitination and Subsequent TGF-β Pathway Activation Promote High-Fat/High-Sucrose Diet-Induced Arterial Stiffness.","authors":"Yanan Liu, Mengke Li, Zhipeng Chen, Min Zuo, Kaiwen Bao, Ziyan Zhao, Meng Yan, Yongping Bai, Ding Ai, Hu Wang, Hongfeng Jiang","doi":"10.1161/CIRCRESAHA.124.325590","DOIUrl":"10.1161/CIRCRESAHA.124.325590","url":null,"abstract":"<p><strong>Background: </strong>Metabolic syndrome heightens cardiovascular disease risk primarily through increased arterial stiffness. We previously demonstrated the involvement of YAP (Yes-associated protein) in high-fat/high-sucrose diet (HFHSD)-induced arterial stiffness via modulation of PPM1B (protein phosphatase Mg²⁺/Mn²⁺-dependent 1B)-lysine 63(K63) deubiquitination. In this study, we aimed to elucidate the role and mechanisms underlying PPM1B deubiquitination in HFHSD-induced arterial stiffness.</p><p><strong>Methods: </strong>Enzymes governing PPM1B deubiquitination were identified through small interfering RNA (siRNA) screening and mass spectrometry. Glutathione S-transferase pull-down, coimmunoprecipitation, protein purification, and immunofluorescence were used to explore the mechanism underlying PPM1B deubiquitination. Doppler ultrasound was used to evaluate HFHSD-induced arterial stiffness in mice, and telemetry was used to record pulsatile (systolic and diastolic) blood pressure.</p><p><strong>Results: </strong>Smooth muscle cell-specific PPM1B overexpression attenuated HFHSD-induced arterial stiffness in mice in a PPM1B-K326-K63-linked polyubiquitination-dependent manner. Mechanistically, ABRO1 (Abraxas brother 1; a core BRCC36 [BRCA1/BRCA2 (breast cancer type 1/2)-containing complex subunit 36] isopeptidase complex component) directly bound YAP and underwent liquid-liquid phase separation with YAP and PPM1B in a YAP-dependent manner, which in turn promoted PPM1B deubiquitination. Furthermore, smooth muscle cell-specific <i>Abro1</i>-knockout mice and <i>Brcc3</i>-knockout mice showed attenuated HFHSD-induced arterial stiffness and activation of transforming growth factor-β-Smad (mothers against decapentaplegic homolog) signaling.</p><p><strong>Conclusions: </strong>We elucidated the PPM1B deubiquitination mechanisms and highlighted a potential therapeutic target for metabolic syndrome-related arterial stiffness.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"297-314"},"PeriodicalIF":16.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913593","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}