Circulation research最新文献

{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000685","DOIUrl":"https://doi.org/10.1161/RES.0000000000000685","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 4","pages":"472-473"},"PeriodicalIF":16.5,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874331","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":"Maternal Diet and Gut Microbiota Influence Predisposition to Cardiovascular Disease in Offspring.","authors":"Hamdi A Jama, Malathi S I Dona, Evany Dinakis, Michael Nakai, Madeleine R Paterson, Waled A Shihata, Crisdion Krstevski, Charles D Cohen, Kate L Weeks, Gabriella E Farrugia, Chad Johnson, Ekaterina Salimova, Daniel G Donner, Helen Kiriazis, Harikrishnan Kaipananickal, Jun Okabe, Dovile Anderson, Darren J Creek, Charles R Mackay, Assam El-Osta, Alexander R Pinto, David M Kaye, Francine Z Marques","doi":"10.1161/CIRCRESAHA.124.324614","DOIUrl":"10.1161/CIRCRESAHA.124.324614","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"537-539"},"PeriodicalIF":16.5,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626200","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":"Ubiquitin Ligase RBX2/SAG Regulates Mitochondrial Ubiquitination and Mitophagy.","authors":"Wenjuan Wang, Ermin Li, Jianqiu Zou, Chen Qu, Juan Ayala, Yuan Wen, Md Sadikul Islam, Neal L Weintraub, David J R Fulton, Qiangrong Liang, Jiliang Zhou, Jinbao Liu, Jie Li, Yi Sun, Huabo Su","doi":"10.1161/CIRCRESAHA.124.324285","DOIUrl":"10.1161/CIRCRESAHA.124.324285","url":null,"abstract":"<p><strong>Background: </strong>Clearance of damaged mitochondria via mitophagy is crucial for cellular homeostasis. Apart from Parkin, little is known about additional Ub (ubiquitin) ligases that mediate mitochondrial ubiquitination and turnover, particularly in highly metabolically active organs such as the heart.</p><p><strong>Methods: </strong>In this study, we have combined in silico analysis and biochemical assay to identify CRL (cullin-RING ligase) 5 as a mitochondrial Ub ligase. We generated cardiomyocytes and mice lacking RBX2 (RING-box protein 2; also known as SAG [sensitive to apoptosis gene]), a catalytic subunit of CRL5, to understand the effects of RBX2 depletion on mitochondrial ubiquitination, mitophagy, and cardiac function. We also performed proteomics analysis and RNA-sequencing analysis to define the impact of loss of RBX2 on the proteome and transcriptome.</p><p><strong>Results: </strong>RBX2 and CUL (cullin) 5, 2 core components of CRL5, localize to mitochondria. Depletion of RBX2 inhibited mitochondrial ubiquitination and turnover, impaired mitochondrial membrane potential and respiration, increased cardiomyocyte cell death, and has a global impact on the mitochondrial proteome. In vivo, deletion of the <i>Rbx2</i> gene in adult mouse hearts suppressed mitophagic activity, provoked accumulation of damaged mitochondria in the myocardium, and disrupted myocardial metabolism, leading to the rapid development of dilated cardiomyopathy and heart failure. Similarly, ablation of RBX2 in the developing heart resulted in dilated cardiomyopathy and heart failure. The action of RBX2 in mitochondria is not dependent on Parkin, and Parkin gene deletion had no impact on the onset and progression of cardiomyopathy in RBX2-deficient hearts. Furthermore, RBX2 controls the stability of PINK1 (PTEN-induced kinase 1) in mitochondria.</p><p><strong>Conclusions: </strong>These findings identify RBX2-CRL5 as a mitochondrial Ub ligase that regulates mitophagy and cardiac homeostasis in a Parkin-independent, PINK1-dependent manner.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e39-e56"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11264309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141316857","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":"Genome-Wide Methylation Analysis Reveals a <i>KCNK3</i>-Prominent Causal Cascade on Hypertension.","authors":"Dandan Huang, Wenlong Shang, Mengtong Xu, Qiangyou Wan, Jin Zhang, Xiaofeng Tang, Yujun Shen, Yan Wang, Ying Yu","doi":"10.1161/CIRCRESAHA.124.324455","DOIUrl":"10.1161/CIRCRESAHA.124.324455","url":null,"abstract":"<p><strong>Background: </strong>Despite advances in understanding hypertension's genetic structure, how noncoding genetic variants influence it remains unclear. Studying their interaction with DNA methylation is crucial to deciphering this complex disease's genetic mechanisms.</p><p><strong>Methods: </strong>We investigated the genetic and epigenetic interplay in hypertension using whole-genome bisulfite sequencing. Methylation profiling in 918 males revealed allele-specific methylation and methylation quantitative trait loci. We engineered rs1275988^T/C mutant mice using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9), bred them for homozygosity, and subjected them to a high-salt diet. Telemetry captured their cardiovascular metrics. Protein-DNA interactions were elucidated using DNA pull-downs, mass spectrometry, and Western blots. A wire myograph assessed vascular function, and analysis of the <i>Kcnk3</i> gene methylation highlighted the mutation's role in hypertension.</p><p><strong>Results: </strong>We discovered that DNA methylation-associated genetic effects, especially in non-cytosine-phosphate-guanine (non-CpG) island and noncoding distal regulatory regions, significantly contribute to hypertension predisposition. We identified distinct methylation quantitative trait locus patterns in the hypertensive population and observed that the onset of hypertension is influenced by the transmission of genetic effects through the demethylation process. By evidence-driven prioritization and in vivo experiments, we unearthed rs1275988 in a cell type-specific enhancer as a notable hypertension causal variant, intensifying hypertension through the modulation of local DNA methylation and consequential alterations in <i>Kcnk3</i> gene expression and vascular remodeling. When exposed to a high-salt diet, mice with the rs1275988^C/C genotype exhibited exacerbated hypertension and significant vascular remodeling, underscored by increased aortic wall thickness. The C allele of rs1275988 was associated with elevated DNA methylation levels, driving down the expression of the <i>Kcnk3</i> gene by attenuating Nr2f2 (nuclear receptor subfamily 2 group F member 2) binding at the enhancer locus.</p><p><strong>Conclusions: </strong>Our research reveals new insights into the complex interplay between genetic variations and DNA methylation in hypertension. We underscore hypomethylation's potential in hypertension onset and identify rs1275988 as a causal variant in vascular remodeling. This work advances our understanding of hypertension's molecular mechanisms and encourages personalized health care strategies.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e76-e93"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260446","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":"A New linc(-RNA) Between NFAT/MEF2 and Cardiac Hypertrophy.","authors":"Chen Gao, Yibin Wang","doi":"10.1161/CIRCRESAHA.124.324794","DOIUrl":"10.1161/CIRCRESAHA.124.324794","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 3","pages":"450-452"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723176","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":"Antiarrhythmic Mechanisms of Epidural Blockade After Myocardial Infarction.","authors":"Jonathan D Hoang, Valerie Y H van Weperen, Ki-Woon Kang, Neil R Jani, Mohammed A Swid, Christopher A Chan, Zulfiqar Ali Lokhandwala, Robert L Lux, Marmar Vaseghi","doi":"10.1161/CIRCRESAHA.123.324058","DOIUrl":"10.1161/CIRCRESAHA.123.324058","url":null,"abstract":"<p><strong>Background: </strong>Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction.</p><p><strong>Methods: </strong>Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (S_max) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation.</p><p><strong>Results: </strong>TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and S_max was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity.</p><p><strong>Conclusions: </strong>TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in S_max, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e57-e75"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466571","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":"Systemic Deletion of ARRDC4 Improves Cardiac Reserve and Exercise Capacity in Diabetes.","authors":"Yoshinobu Nakayama, Satoru Kobayashi, Aliya Masihuddin, Syed Amir Abdali, A M Pramodh Bandara Seneviratne, Sachiyo Ishii, Jun Iida, Qiangrong Liang, Jun Yoshioka","doi":"10.1161/CIRCRESAHA.123.323158","DOIUrl":"10.1161/CIRCRESAHA.123.323158","url":null,"abstract":"<p><strong>Background: </strong>Exercise intolerance is an independent predictor of poor prognosis in diabetes. The underlying mechanism of the association between hyperglycemia and exercise intolerance remains undefined. We recently demonstrated that the interaction between ARRDC4 (arrestin domain-containing protein 4) and GLUT1 (glucose transporter 1) regulates cardiac metabolism.</p><p><strong>Methods: </strong>To determine whether this mechanism broadly impacts diabetic complications, we investigated the role of ARRDC4 in the pathogenesis of diabetic cardiac/skeletal myopathy using cellular and animal models.</p><p><strong>Results: </strong>High glucose promoted translocation of MondoA into the nucleus, which upregulated <i>Arrdc4</i> transcriptional expression, increased lysosomal GLUT1 trafficking, and blocked glucose transport in cardiomyocytes, forming a feedback mechanism. This role of <i>ARRDC4</i> was confirmed in human muscular cells from type 2 diabetic patients. Prolonged hyperglycemia upregulated myocardial <i>Arrdc4</i> expression in multiple types of mouse models of diabetes. We analyzed hyperglycemia-induced cardiac and skeletal muscle abnormalities in insulin-deficient mice. Hyperglycemia increased advanced glycation end-products and elicited oxidative and endoplasmic reticulum stress leading to apoptosis in the heart and peripheral muscle. Deletion of <i>Arrdc4</i> augmented tissue glucose transport and mitochondrial respiration, protecting the heart and muscle from tissue damage. Stress hemodynamic analysis and treadmill exhaustion test uncovered that <i>Arrdc4</i>-knockout mice had greater cardiac inotropic/chronotropic reserve with higher exercise endurance than wild-type animals under diabetes. While multiple organs were involved in the mechanism, cardiac-specific overexpression using an adenoassociated virus suggests that high levels of myocardial <i>ARRDC4</i> have the potential to contribute to exercise intolerance by interfering with cardiac metabolism through its interaction with GLUT1 in diabetes. Importantly, the <i>ARRDC4</i> mutation mouse line exhibited greater exercise tolerance, showing the potential therapeutic impact on diabetic cardiomyopathy by disrupting the interaction between ARRDC4 and GLUT1.</p><p><strong>Conclusions: </strong>ARRDC4 regulates hyperglycemia-induced toxicities toward cardiac and skeletal muscle, revealing a new molecular framework that connects hyperglycemia to cardiac/skeletal myopathy to exercise intolerance.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"416-433"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466572","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.0000000000000683","DOIUrl":"https://doi.org/10.1161/RES.0000000000000683","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"135 3","pages":"414-415"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723177","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":"Therapeutic Inhibition of <i>LincRNA-p21</i> Protects Against Cardiac Hypertrophy.","authors":"Yi Wang, Mingming Zhang, Rong Wang, Jing Lin, Qing Ma, Haipeng Guo, Huihui Huang, Zhuomin Liang, Yangpo Cao, Xiaoran Zhang, Yao Wei Lu, Jianming Liu, Feng Xiao, Hualin Yan, Nadya Dimitrova, Zhan-Peng Huang, John D Mably, William T Pu, Da-Zhi Wang","doi":"10.1161/CIRCRESAHA.123.323356","DOIUrl":"10.1161/CIRCRESAHA.123.323356","url":null,"abstract":"<p><strong>Background: </strong>Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. Recent studies have implicated long noncoding RNAs in cardiac hypertrophy and cardiomyopathy, but their significance and mechanism(s) of action are not well understood.</p><p><strong>Methods: </strong>We measured <i>lincRNA-p21</i> RNA and H3K27ac levels in the hearts of dilated cardiomyopathy patients. We assessed the functional role of <i>lincRNA-p21</i> in basal and surgical pressure-overload conditions using loss-of-function mice. Genome-wide transcriptome analysis revealed dysregulated genes and pathways. We labeled proteins in proximity to full-length lincRNA-p21 using a novel BioID2-based system. We immunoprecipitated lincRNA-p21-interacting proteins and performed cell fractionation, ChIP-seq (chromatin immunoprecipitation followed by sequencing), and co-immunoprecipitation to investigate molecular interactions and underlying mechanisms. We used GapmeR antisense oligonucleotides to evaluate the therapeutic potential of <i>lincRNA-p21</i> inhibition in cardiac hypertrophy and associated heart failure.</p><p><strong>Results: </strong><i>lincRNA-p21</i> was induced in mice and humans with cardiomyopathy. Global and cardiac-specific <i>lincRNA-p21</i> knockout significantly suppressed pressure overload-induced ventricular wall thickening, stress marker elevation, and deterioration of cardiac function. Genome-wide transcriptome analysis and transcriptional network analysis revealed that <i>lincRNA-p21</i> acts <i>in trans</i> to stimulate the NFAT/MEF2 (nuclear factor of activated T cells/myocyte enhancer factor-2) pathway. Mechanistically, lincRNA-p21 is bound to the scaffold protein KAP1 (KRAB-associated protein-1). <i>lincRNA-p21</i> cardiac-specific knockout suppressed stress-induced nuclear accumulation of KAP1, and KAP1 knockdown attenuated cardiac hypertrophy and NFAT activation. KAP1 positively regulates pathological hypertrophy by physically interacting with NFATC4 to promote the overactive status of NFAT/MEF2 signaling. GapmeR antisense oligonucleotide depletion of lincRNA-p21 similarly inhibited cardiac hypertrophy and adverse remodeling, highlighting the therapeutic potential of inhibiting <i>lincRNA-p21</i>.</p><p><strong>Conclusions: </strong>These findings advance our understanding of the functional significance of stress-induced long noncoding RNA in cardiac hypertrophy and demonstrate the potential of <i>lincRNA-p21</i> as a novel therapeutic target for cardiac hypertrophy and subsequent heart failure.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"434-449"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305551","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":"Fibroblast Smad7 Induction Protects the Remodeling Pressure-Overloaded Heart.","authors":"Claudio Humeres, Arti V Shinde, Izabela Tuleta, Silvia C Hernandez, Anis Hanna, Shuaibo Huang, Harikrishnan Venugopal, Jennifer T Aguilan, Simon J Conway, Simone Sidoli, Nikolaos G Frangogiannis","doi":"10.1161/CIRCRESAHA.123.323360","DOIUrl":"10.1161/CIRCRESAHA.123.323360","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cardiac fibroblast activation contributes to adverse remodeling, fibrosis, and dysfunction in the pressure-overloaded heart. Although early fibroblast TGF-β (transforming growth factor-β)/Smad (small mother against decapentaplegic)-3 activation protects the pressure-overloaded heart by preserving the matrix, sustained TGF-β activation is deleterious, accentuating fibrosis and dysfunction. Thus, endogenous mechanisms that negatively regulate the TGF-β response in fibroblasts may be required to protect from progressive fibrosis and adverse remodeling. We hypothesized that Smad7, an inhibitory Smad that restrains TGF-β signaling, may be induced in the pressure-overloaded myocardium and may regulate fibrosis, remodeling, and dysfunction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;The effects of myofibroblast-specific Smad7 loss were studied in a mouse model of transverse aortic constriction, using echocardiography, histological analysis, and molecular analysis. Proteomic studies in S7KO (Smad7 knockout) and overexpressing cells were used to identify fibroblast-derived mediators modulated by Smad7. In vitro experiments using cultured cardiac fibroblasts, fibroblasts populating collagen lattices, and isolated macrophages were used to dissect the molecular signals responsible for the effects of Smad7.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Following pressure overload, Smad7 was upregulated in cardiac myofibroblasts. TGF-β and angiotensin II stimulated fibroblast Smad7 upregulation via Smad3, whereas GDF15 (growth differentiation factor 15) induced Smad7 through GFRAL (glial cell line-derived neurotrophic factor family receptor α-like). MFS7KO (myofibroblast-specific S7KO) mice had increased mortality, accentuated systolic dysfunction and dilative remodeling, and accelerated diastolic dysfunction in response to transverse aortic constriction. Increased dysfunction in MFS7KO hearts was associated with accentuated fibrosis and increased MMP (matrix metalloproteinase)-2 activity and collagen denaturation. Secretomic analysis showed that Smad7 loss accentuates secretion of structural collagens and matricellular proteins and markedly increases MMP2 secretion. In contrast, Smad7 overexpression reduced MMP2 levels. In fibroblasts populating collagen lattices, the effects of Smad7 on fibroblast-induced collagen denaturation and pad contraction were partly mediated via MMP2 downregulation. Surprisingly, MFS7KO mice also exhibited significant macrophage expansion caused by paracrine actions of Smad7 null fibroblasts that stimulate macrophage proliferation and fibrogenic activation. Macrophage activation involved the combined effects of the fibroblast-derived matricellular proteins CD5L (CD5 antigen-like), SPARC (secreted protein acidic and rich in cysteine), CTGF (connective tissue growth factor), ECM1 (extracellular matrix protein 1), and TGFBI (TGFB induced).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;The antifibrotic effects of Smad7 in the pressure-over","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"453-469"},"PeriodicalIF":16.5,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11257802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141426428","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}