Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Roles of Brd4 in Vascular Smooth Muscle Cells: Implications for Aging and Vascular Dysfunction.","authors":"Jiaxing Sun, Yu Gui, Hao Yin, Binjie Yan, Yong-Xiang Chen, Darrell D Belke, Joseph A Hill, Shenghua Zhou, Xi-Long Zheng","doi":"10.1161/ATVBAHA.124.322158","DOIUrl":"10.1161/ATVBAHA.124.322158","url":null,"abstract":"<p><strong>Background: </strong>Growing evidence suggests that the epigenetic reader Brd4 (bromodomain-containing protein 4) is involved in aging and aging-related diseases. However, the specific mechanisms by which Brd4 influences vascular aging, especially senescence of vascular smooth muscle cells (SMCs), remain unexplored.</p><p><strong>Methods: </strong>Primary cell cultures were established using mouse aortic SMCs and treated with Brd4 inhibitor, ARV-825, or (+)-JQ1. Primary Brd4^flox/flox mouse aortic SMCs were transduced with Ad-Cre virus to induce Brd4 knockout (KO). Senescence was assessed through SA-β-gal (senescence-associated β-galactosidase) staining. A mouse model of inducible SMC-specific Brd4 gene KO (SMC-Brd4-KO) was generated with the Cre-LoxP system. The control and SMC-Brd4-KO mice were evaluated for arterial contractility, blood pressure, arterial stiffness, and Ang II (angiotensin II)-induced vascular aging, as well as transcriptome profiling using RNA-sequencing analysis.</p><p><strong>Results: </strong>Brd4 inhibition with ARV-825, (+)-JQ1, or Brd4 knockdown through Ad-Cre virus in Brd4^flox/flox SMCs led to cellular senescence. Induced SMC-Brd4-KO in adult mice prevented neointima formation. SMC-Brd4-KO mice exhibited increased aortic stiffness and blood pressure with enhanced arterial contractility ex vivo. In addition, Brd4 expression was downregulated in aortic tissues of aged mice and senescent human aortic SMCs. Furthermore, SMC-Brd4-KO mice displayed more prominent histopathologic features of vascular aging in response to Ang II infusion. Aortic tissues from SMC-Brd4-KO mice showed a more robust contractile response to Ang II and phenylephrine, accompanied by multiple genetic changes, including alterations in cytoskeleton genes. Transcriptomes of Brd4 KO aortas displayed gene signatures of dampened autophagy, intriguingly associated with a downregulation of microtubule genes, including <i>Tuba4a</i> (α-tubulin). Experiments in vitro with Brd4 KO SMCs demonstrated the potential role of impaired autophagy and depleted α-tubulin in mediating induction of senescence in SMCs.</p><p><strong>Conclusions: </strong>Brd4 depletion in SMCs induces senescence, prevents neointima formation, and exacerbates vascular aging, highlighting its crucial roles in vascular functions and diseases.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e250-e270"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118685","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":"Extracellular Vesicles at the Helm: Steering the Pathogenesis and Treatment of Atherosclerosis.","authors":"Robert L Raffai","doi":"10.1161/ATVBAHA.125.323025","DOIUrl":"https://doi.org/10.1161/ATVBAHA.125.323025","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 7","pages":"1306-1309"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493824","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":"Placental Vascular Defects and Embryonic Lethality Triggered by TFPIα Deficiency in Factor V Leiden Mice.","authors":"Amy E Siebert, Susan A Maroney, Nicholas D Martinez, Michael J Soares, Alan E Mast","doi":"10.1161/ATVBAHA.125.322650","DOIUrl":"10.1161/ATVBAHA.125.322650","url":null,"abstract":"<p><strong>Background: </strong>TFPI (tissue factor pathway inhibitor) inhibits the initiation of blood coagulation. TFPIα (TFPI alpha isoform), the only alternatively spliced TFPI isoform in platelets, is abundant in placenta and uniquely inhibits prothrombinase (FXa [activated factor X]-FVa [activated factor V]). This inhibitory activity is reduced when prothrombinase is assembled with FVL (factor V Leiden).</p><p><strong>Methods: </strong>Effects of TFPIα (<i>Tfpi</i>^Δα) and platelet (<i>Tfpi</i>^fl; <i>Pf4</i>-Cre⁺) specific knockout alleles were characterized in FVL (<i>F5</i>^L) mice to examine the physiological effects of the TFPIα-FV interaction.</p><p><strong>Results: </strong>Genotype frequencies were assessed and revealed that <i>Tfpi</i>^+/Δα <i>F5</i>^L/L mice survive to adulthood. However, <i>Tfpi</i>^Δα homozygosity with even a single <i>F5</i>^L allele resulted in embryonic lethality during mid-gestation development regardless of maternal FVL status. In contrast, <i>F5</i>^L/L <i>Tfpi</i>^fl/fl <i>Pf4</i>-Cre⁺ mice were at expected frequencies at weaning, indicating that platelet TFPIα loss alone did not cause mid-gestation lethality in <i>Tfpi</i>^Δα/Δα <i>F5</i>^L mice. Histological analyses showed no fibrin deposition in embryonic or extraembryonic tissues but revealed placental vasculature defects in <i>Tfpi</i>^Δα/Δα <i>F5</i>^L genotypes. Treatment with the direct thrombin inhibitor dabigatran partially rescued the lethality and corrected placental defects, implicating excessive thrombin generation as a factor in <i>Tfpi</i>^Δα/Δα <i>F5</i>^L demise.</p><p><strong>Conclusions: </strong>These findings suggest that TFPIα and its inhibition of prothrombinase play an important role in placental angiogenesis and embryonic survival.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1266-1276"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118684","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":"TRPV4 Channel Contributes to Aortic Root Stiffening and Atherosclerotic Lesion Development.","authors":"Suneha G Rahaman, Bidisha Dutta, Zhenguo Liu, Shaik O Rahaman","doi":"10.1161/ATVBAHA.125.322640","DOIUrl":"10.1161/ATVBAHA.125.322640","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1337-1339"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960453","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":"Role of Hemoglobin-Stimulated Macrophages and Intraplaque Hemorrhage in the Development of Vascular Diseases.","authors":"Atsushi Sakamoto, Alyssa Grogan, Rika Kawakami, Alexandra Finn, Palak Shah, Diya Nair, Krish Batra, Caroline Bailen, Mirai Sakamoto, Renu Virmani, Aloke V Finn","doi":"10.1161/ATVBAHA.125.321439","DOIUrl":"10.1161/ATVBAHA.125.321439","url":null,"abstract":"<p><p>Intraplaque hemorrhage plays a critical role in the life of advancing atherosclerotic plaques, not only by triggering an acute increase in lesion size but also by attracting macrophages to the site. Lysis of erythrocytes in these areas is thought to be caused by oxidative stress, which induces the release of free Hb (hemoglobin), which is quickly bound by haptoglobin to form Hb-haptoglobin complexes. Macrophages are the only cells in the body capable of scavenging these complexes through the CD (cluster of differentiation) 163 scavenger receptor, which mediates Hb-haptoglobin ingestion, driving their differentiation. Emerging data suggest that these Hb-stimulated macrophages play an essential role in responding to intraplaque hemorrhage through mediating iron metabolism and influencing other cell types, including endothelial and smooth muscle cells. This review focuses on the role of Hb-stimulated macrophages in promoting atherogenesis through their effects on (1) endothelial activation, neoangiogenesis, and vascular permeability; (2) endothelial-to-mesenchymal cell transition and subsequent apoptosis; and (3) the prevention of smooth muscle cell osteogenic transformation and calcification. These functions may also be relevant to other vascular diseases where erythrocyte accumulation drives the formation of Hb-stimulated macrophages, which is a fundamental response to hemorrhage no matter the clinical setting.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1021-1030"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970193","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":"Exercise-Stimulated Resolvin Biosynthesis in the Adipose Tissue Is Abrogated by High-Fat Diet-Induced Adrenergic Deficiency.","authors":"Ernesto Pena Calderin, Jing-Juan Zheng, Nolan L Boyd, Will Lynch, Brian E Sansbury, Matthew Spite, Bradford G Hill, Jason Hellmann","doi":"10.1161/ATVBAHA.124.322234","DOIUrl":"10.1161/ATVBAHA.124.322234","url":null,"abstract":"<p><strong>Background: </strong>Diet-induced white adipose tissue inflammation is associated with insulin resistance and metabolic perturbations. Conversely, exercise protects against the development of diet-induced chronic inflammation and insulin resistance independent of weight loss; however, the mechanisms remain largely unknown. We have recently shown that through adrenergic stimulation of macrophages, exercise promotes resolution of acute peritoneal inflammation by enhancing the biosynthesis of specialized proresolving lipid mediators. In this study, we sought to determine whether exercise stimulates proresolving pathways in adipose tissue and whether this response is modified by diet. Specifically, we hypothesized that exercise stimulates proresolving pathways by adrenergic signaling, which is inhibited by high-fat diet, priming the development of chronic inflammation in the adipose tissue.</p><p><strong>Methods: </strong>To explore the dietary dependence of the proresolving effects of exercise, mice were fed either a control or high-fat diet for 2 weeks before, and throughout, a 4-week period of daily treadmill running. Glucose handling, body weight and composition, lipemia, and exercise performance were evaluated at the end of the feeding and exercise interventions. Likewise, changes in catecholamines and their biosynthetic enzymes were measured along with adipose tissue specialized proresolving lipid mediator levels and macrophage phenotype and abundance.</p><p><strong>Results: </strong>When compared with sedentary controls, macrophages isolated from mice exposed to 4 weeks of exercise display elevated expression of the specialized proresolving lipid mediator biosynthetic enzyme <i>Alox15</i>, while adipose tissue specialized proresolving lipid mediator levels and anti-inflammatory CD301⁺ M2 macrophages increased. These changes were dependent upon diet as 6 weeks of feeding with high-fat diet abrogated the proresolving effect of exercise when compared with control diet-fed animals. Interestingly, exercise-induced epinephrine production was inhibited by high-fat diet, which diminished the expression of the epinephrine biosynthetic enzyme PNMT (phenylethanolamine N-methyltransferase) in adrenal glands.</p><p><strong>Conclusions: </strong>Taken together, these results suggest that a diet high in fat diminishes the proresolving effects of exercise in the adipose tissue via decreasing the biosynthesis of catecholamines.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1090-1110"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957264","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":"Fluorescence-Activated Cell Sorting Depletes Macrophages and Triggers Inflammation in the Single-Cell Immune Landscape of Human Atherosclerosis.","authors":"Ayden G Case, James W O'Brien, Fiona T W Charlier, Ali B A K Al-Hadithi, Mohammed M Chowdhury, Stephen A Newland, Zixuan Huang, Gemma Basatemur, Xiaohui Zhao, Ayoola I Awopetu, Jonathan R Boyle, Nicholas R Evans, Ziad Mallat, Tian X Zhao","doi":"10.1161/ATVBAHA.125.322856","DOIUrl":"10.1161/ATVBAHA.125.322856","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1340-1342"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188805/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224168","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":"Impaired CAMK4 Activity Limits Atherosclerosis and Reprograms Myelopoiesis.","authors":"Azuah L Gonzalez, Cristina M Youwakim, Brenda F Leake, Kristin K Fuller, S M Jamshedur Rahman, Matthew M Dungan, Katherine Gu, Jesse L Bonin, Ashley B Cavnar, Danielle L Michell, Lindsay M Davison, Calliope Cutchins, Yunli E Chu, Shuai Yuan, Arif Yurdagul, James G Traylor, A Wayne Orr, Zachary A Kohutek, MacRae F Linton, Katherine C MacNamara, P Brent Ferrell, Kasey C Vickers, Meena S Madhur, Jonathan D Brown, Amanda C Doran","doi":"10.1161/ATVBAHA.125.322530","DOIUrl":"10.1161/ATVBAHA.125.322530","url":null,"abstract":"<p><strong>Background: </strong>Chronic inflammation is a major driver of atherosclerotic cardiovascular disease, and therapeutics that target inflammation reduce cardiac events beyond levels seen with strategies targeting cholesterol alone. RNA sequencing revealed increased expression of CaMK4 (calcium/calmodulin-dependent protein kinase IV) in advanced/unstable human carotid artery plaque. We validated this finding in mouse and human atherosclerotic lesions, demonstrating increased CaMK4 in plaque macrophages. Therefore, we hypothesized that CaMK4 would promote inflammation and impair resolution in atherosclerosis.</p><p><strong>Methods: </strong>We obtained mice in which exon 3 within the kinase domain of CaMK4 is deleted, leading to degradation and deletion of the gene (<i>Camk4</i>^<i>-/-</i>). Control and <i>Camk4</i>^<i>-/-</i> mice were injected with a gain-of-function AAV (adeno-associated virus) 8-PCSK9 (proprotein convertase subtilisin/kexin type 9) virus, rendering them hypercholesterolemic, and fed a high-fat/high-cholesterol diet for 12 weeks.</p><p><strong>Results: </strong>Hypercholesterolemic <i>Camk4</i>^<i>-/-</i> mice developed smaller and more stable lesions compared with control mice. Surprisingly, <i>Camk4</i>^<i>-/-</i> mice had a peripheral monocytosis with skewing of monocyte populations toward the nonclassical Ly6c^low subset, suggesting a less inflammatory monocyte population. Silencing or inhibition of CaMK4 in human monocytes recapitulated this phenotype. In response to hypercholesterolemia, which promotes myelopoiesis, <i>Camk4</i>^<i>-/-</i> mice had markedly more myeloid progenitors. <i>Camk4</i>^<i>-/-</i> monocytes expressed higher levels of genes associated with myeloid differentiation and recruitment of ATF6 (activating transcription factor 6) to conserved binding sites. In addition, <i>Camk4</i>^<i>-/-</i> monocytes expressed higher levels of <i>Nr4a1</i>, which promotes conversion of Ly6c^high to Ly6c^low monocytes. <i>Camk4</i>^<i>-/-</i> monocytes failed to efficiently traffic in vitro and in vivo. Bone marrow-derived macrophages generated from <i>Camk4</i>^<i>-/-</i> marrow had a more proreparative phenotype than control macrophages, consistent with our in vivo observations in the plaque.</p><p><strong>Conclusions: </strong>These findings suggest that CaMK4 is an important regulator of the myelopoietic response to hypercholesterolemia through ATF6-mediated transcriptional regulation and that loss of functional CaMK4 promotes a proreparative phenotype in myeloid cells. Therefore, targeting CaMK4 may offer a unique way to target the progression of atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e286-e306"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12197841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953601","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":"Single-Cell and Spatial Transcriptomics Identified Fatty Acid-Binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension.","authors":"Bin Liu, Dan Yi, Shuai Li, Karina Ramirez, Xiaomei Xia, Yanhong Cao, Hanqiu Zhao, Ankit Tripathi, Shenfeng Qiu, Mrinalini Kala, Ruslan Rafikov, Haiwei Gu, Vinicio de Jesus Perez, Sarah-Eve Lemay, Christopher C Glembotski, Kenneth S Knox, Sebastien Bonnet, Vladimir V Kalinichenko, You-Yang Zhao, Michael B Fallon, Olivier Boucherat, Zhiyu Dai","doi":"10.1161/ATVBAHA.124.321173","DOIUrl":"10.1161/ATVBAHA.124.321173","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for patients with PAH. Recent studies showed that FABP (fatty acid-binding protein) 4 and FABP5 are expressed in endothelial cells (ECs) across multiple tissues, and circulating FABP4 level is elevated in patients with PAH. However, the role of endothelial FABP4/5 in the pathogenesis of PAH remains undetermined.</p><p><strong>Methods: </strong>FABP4/5 expression was examined in pulmonary arterial ECs and lung tissues from patients with idiopathic PAH and pulmonary hypertension (PH) rat models. Plasma proteome analysis was performed in human PAH samples. Echocardiography, hemodynamics, histology, and immunostaining were performed to evaluate the lung and heart PH phenotypes in <i>Egln1</i>^{<i>Tie2Cre</i>} (CKO) mice and <i>Egln1</i>^{<i>Tie2Cre</i>}<i>/Fabp4/5</i>^<i>-/-</i> (TKO) mice. Bulk RNA sequencing (RNA-seq), single-cell RNA sequencing analysis, and spatial transcriptomic analysis were performed to understand the cellular and molecular mechanisms of endothelial FABP4/5-mediated PAH pathogenesis.</p><p><strong>Results: </strong>Both FABP4 and FABP5 were highly induced in ECs of CKO mice and pulmonary arterial ECs from patients with idiopathic PAH (IPAH) and in whole lungs of PH rats. Plasma levels of FABP4/5 were upregulated in patients with IPAH and directly correlated with severity of hemodynamics and biochemical parameters. Genetic deletion of both <i>Fabp4</i> and <i>Fabp5</i> in CKO mice caused a reduction of right ventricular systolic pressure and right ventricular hypertrophy, attenuated pulmonary vascular remodeling, and prevented the right heart failure secondary to PH. FABP4/5 deletion also normalized EC glycolysis and distal arterial programming, reduced reactive oxygen species and HIF (hypoxia-inducible factor)-2α expression, and decreased aberrant EC proliferation in CKO lungs.</p><p><strong>Conclusions: </strong>PH causes aberrant expression of FABP4/5 in pulmonary ECs, which leads to enhanced EC glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1145-1165"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12188824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118686","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":"PARylation of POLG Mediated by PARP1 Accelerates Ferroptosis-Induced Vascular Calcification via Activating Adora2a/Rap1 Signaling.","authors":"Yiqing Yang, Xiaoxue Li, Shengjue Xiao, Qin Wei, Liqun Ren, Yuyu Yao, Naifeng Liu","doi":"10.1161/ATVBAHA.124.321682","DOIUrl":"10.1161/ATVBAHA.124.321682","url":null,"abstract":"<p><strong>Background: </strong>Vascular calcification (VC) is associated with diabetes, chronic kidney disease, and aging. VC is found to be a powerful and independent risk factor for cardiovascular mortality. Vascular smooth muscle cell (VSMC) ferroptosis, a form of cell death, is known to be involved in VC. However, whether VSMC ferroptosis is regulated by posttranslational modifications remains undefined.</p><p><strong>Methods: </strong>We explored the potential role and mechanism of PARP1 (poly[ADP-ribose] polymerase 1)-mediated poly(ADP-ribosyl)ation (PARylation) in VSMC ferroptosis during VC. Mouse VSMCs were treated with β-glycerophosphate, and Parp1^flox/flox Tagln Cre⁺ calcified mice were generated with AAV9-sh-POLG (DNA polymerase gamma) injected to establish in vitro and in vivo models, respectively. RNA-sequencing analysis was performed to determine the transcriptomic alterations in VSMCs overexpressing POLG and treated with β-glycerophosphate.</p><p><strong>Results: </strong>Both PARP1 expression and PARylation levels were increased in β-glycerophosphate-induced VC, with PARP1 knockdown mitigating VC by improving mitochondrial function and inhibiting the subsequent VSMC ferroptosis. Mechanistically, POLG PARylation levels were increased in calcified VSMCs from PARP1 activation, triggering PARylation-dependent ubiquitination of POLG that resulted in POLG downregulation. This led to mitochondrial dysfunction and Adora2a (adenosine receptor A2A)/Rap1 (Ras-associated protein 1) signaling pathway activation to induce VSMC ferroptosis, which ultimately aggravated VC.</p><p><strong>Conclusions: </strong>Our study establishes the critical role of PARP1-mediated PARylation-dependent ubiquitination of POLG in VSMC ferroptosis-induced VC. These findings suggest that PARP1 inhibitors could potentially serve as novel therapeutic strategies for VC.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"1175-1191"},"PeriodicalIF":7.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118683","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}