Publisher: American Heart Association   (Total: 12 journals)   [Sort by number of followers]

Showing 1 - 12 of 12 Journals sorted alphabetically
Arteriosclerosis, Thrombosis and Vascular Biology     Full-text available via subscription   (Followers: 28, SJR: 3.435, CiteScore: 5)
Circulation     Hybrid Journal   (Followers: 183, SJR: 8.95, CiteScore: 9)
Circulation : Arrhythmia and Electrophysiology     Hybrid Journal   (Followers: 14, SJR: 3.225, CiteScore: 4)
Circulation : Cardiovascular Imaging     Hybrid Journal   (Followers: 18, SJR: 3.242, CiteScore: 4)
Circulation : Cardiovascular Interventions     Hybrid Journal   (Followers: 23, SJR: 4.228, CiteScore: 5)
Circulation : Cardiovascular Quality and Outcomes     Hybrid Journal   (Followers: 14, SJR: 2.743, CiteScore: 3)
Circulation : Genomic and Precision Medicine     Hybrid Journal   (Followers: 11, SJR: 2.661, CiteScore: 4)
Circulation : Heart Failure     Hybrid Journal   (Followers: 27, SJR: 4.2, CiteScore: 5)
Circulation Research     Hybrid Journal   (Followers: 32, SJR: 6.813, CiteScore: 9)
Hypertension     Full-text available via subscription   (Followers: 27)
J. of the American Heart Association     Open Access   (Followers: 19, SJR: 2.674, CiteScore: 4)
Stroke     Hybrid Journal   (Followers: 92, SJR: 3.529, CiteScore: 5)
Similar Journals
Journal Cover
Circulation Research
Journal Prestige (SJR): 6.813
Citation Impact (citeScore): 9
Number of Followers: 32  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0009-7330 - ISSN (Online) 1524-4571
Published by American Heart Association Homepage  [12 journals]
  • In this Issue

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      Authors: Ruth Williams
      First page: 1487
      Abstract: Circulation Research, Volume 130, Issue 10, Page 1487, May 13, 2022.

      Citation: Circulation Research
      PubDate: 2022-05-12T06:00:05Z
      DOI: 10.1161/RES.0000000000000552
      Issue No: Vol. 130, No. 10 (2022)
       
  • Meet the First Authors

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      Pages: 1488 - 1489
      Abstract: Circulation Research, Volume 130, Issue 10, Page 1488-1489, May 13, 2022.

      Citation: Circulation Research
      PubDate: 2022-05-12T06:00:05Z
      DOI: 10.1161/RES.0000000000000553
      Issue No: Vol. 130, No. 10 (2022)
       
  • Cardio-Protective Messengers From “Good Fat”

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      Authors: Chen Gao Yibin Wang Department of Pharmacology; Metabolic Diseases, Duke-NUS, Singapore (Y.W.).
      Pages: 1507 - 1509
      Abstract: Circulation Research, Volume 130, Issue 10, Page 1507-1509, May 13, 2022.

      Citation: Circulation Research
      PubDate: 2022-05-12T06:00:05Z
      DOI: 10.1161/CIRCRESAHA.122.321143
      Issue No: Vol. 130, No. 10 (2022)
       
  • Piezo1 Tunes Blood Flow in the Central Nervous System

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      Authors: Robert H. Cudmore L. Fernando Santana Department of Physiology; Membrane Biology, University of California-Davis School of Medicine.
      Pages: 1547 - 1549
      Abstract: Circulation Research, Volume 130, Issue 10, Page 1547-1549, May 13, 2022.

      Citation: Circulation Research
      PubDate: 2022-05-12T06:00:05Z
      DOI: 10.1161/CIRCRESAHA.122.321144
      Issue No: Vol. 130, No. 10 (2022)
       
  • Lnc’ing Metabolic Regulation of Epigenetic Modifications to
           Atherosclerotic Calcification

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      Authors: Rolando A. Cuevas Cynthia St. Hilaire Departments of Medicine; Blood Vascular Medicine Institute, University of Pittsburgh, PA.
      Pages: 1583 - 1585
      Abstract: Circulation Research, Volume 130, Issue 10, Page 1583-1585, May 13, 2022.

      Citation: Circulation Research
      PubDate: 2022-05-12T06:00:05Z
      DOI: 10.1161/CIRCRESAHA.122.321142
      Issue No: Vol. 130, No. 10 (2022)
       
  • Cardiorenal Syndrome: The Role of Neural Connections Between the Heart and
           the Kidneys

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      Authors: Kaushik P. Patel Kenichi Katsurada Hong Zheng Department of Cellular; Integrative Physiology, University of Nebraska Medical Center, Omaha (K.P.P.). Division of Cardiovascular Medicine, Department of Internal Medicine (K.K.), Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan. Division of Clinical Pharmacology, Department of Pharmacology (K.K.), Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan. Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion (H.Z.).
      Pages: 1601 - 1617
      Abstract: Circulation Research, Volume 130, Issue 10, Page 1601-1617, May 13, 2022.
      The maintenance of cardiovascular homeostasis is highly dependent on tightly controlled interactions between the heart and the kidneys. Therefore, it is not surprising that a dysfunction in one organ affects the other. This interlinking relationship is aptly demonstrated in the cardiorenal syndrome. The characteristics of the cardiorenal syndrome state include alterations in neurohumoral drive, autonomic reflexes, and fluid balance. The evidence suggests that several factors contribute to these alterations. These may include peripheral and central nervous system abnormalities. However, accumulating evidence from animals with experimental models of congestive heart failure and renal dysfunction as well as humans with the cardiorenal syndrome suggests that alterations in neural pathways, from and to the kidneys and the heart, including the central nervous system are involved in regulating sympathetic outflow and may be critically important in the alterations in neurohumoral drive, autonomic reflexes, and fluid balance commonly observed in the cardiorenal syndrome. This review focuses on studies implicating neural pathways, particularly the afferent and efferent signals from the heart and the kidneys integrating at the level of the paraventricular nucleus in the hypothalamus to alter neurohumoral drive, autonomic pathways, and fluid balance. Further, it explores the potential mechanisms of action for the known beneficial use of various medications or potential novel therapeutic manipulations for the treatment of the cardiorenal syndrome. A comprehensive understanding of these mechanisms will enhance our ability to treat cardiorenal conditions and their cardiovascular complications more efficaciously and thoroughly.
      Citation: Circulation Research
      PubDate: 2022-05-12T06:00:05Z
      DOI: 10.1161/CIRCRESAHA.122.319989
      Issue No: Vol. 130, No. 10 (2022)
       
  • Emerging Viral Infections and the Potential Impact on Hypertension,
           Cardiovascular Disease, and Kidney Disease

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      Authors: Solomiia Savedchuk Rasha Raslan Sarah Nystrom Matthew A. Sparks Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC (S.S; S.N, M.A.S.). Renal Section, Durham VA Health Care System, NC (M.A.S.). Internal Medicine, Virginia Commonwealth University, Richmond (R.R.).
      Pages: 1618 - 1641
      Abstract: Circulation Research, Volume 130, Issue 10, Page 1618-1641, May 13, 2022.
      Viruses are ubiquitous in the environment and continue to have a profound impact on human health and disease. The COVID-19 pandemic has highlighted this with impressive morbidity and mortality affecting the world’s population. Importantly, the link between viruses and hypertension, cardiovascular disease, and kidney disease has resulted in a renewed focus and attention on this potential relationship. The virus responsible for COVID-19, SARS-CoV-2, has a direct link to one of the major enzymatic regulatory systems connected to blood pressure control and hypertension pathogenesis, the renin-angiotensin system. This is because the entry point for SARS-CoV-2 is the ACE2 (angiotensin-converting enzyme 2) protein. ACE2 is one of the main enzymes responsible for dampening the primary effector peptide Ang II (angiotensin II), metabolizing it to Ang-(1-7). A myriad of clinical questions has since emerged and are covered in this review. Several other viruses have been linked to hypertension, cardiovascular disease, and kidney health. Importantly, patients with high-risk apolipoprotein L1 (APOL1) alleles are at risk for developing the kidney lesion of collapsing glomerulopathy after viral infection. This review will highlight several emerging viruses and their potential unique tropisms for the kidney and cardiovascular system. We focus on SARS-CoV-2 as this body of literature in regards to cardiovascular disease has advanced significantly since the COVID-19 pandemic.
      Citation: Circulation Research
      PubDate: 2022-05-12T06:00:05Z
      DOI: 10.1161/CIRCRESAHA.122.320873
      Issue No: Vol. 130, No. 10 (2022)
       
  • ATF4 Protects the Heart From Failure by Antagonizing Oxidative Stress

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      Authors: Xiaoding Wang Guangyu Zhang Subhajit Dasgupta Erica L. Niewold Chao Li Qinfeng Li Xiang Luo Lin Tan Anwarul Ferdous Philip L. Lorenzi Beverly A. Rothermel Thomas G. Gillette Christopher M. Adams Philipp E. Scherer Joseph A. Hill Zhao V. Wang Department of Cardiology; Renmin Hospital of Wuhan University, Hubei, China (X.W.). Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas. (X.W., G.Z., S.D., E.L.N., C.L., Q.L., X.L., A.F., B.A.R., T.G.G., J.A.H., Z.V.W.) Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas. (B.A.R., J.A.H.) Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas. (P.E.S.) Metabolomics Core Facility, Department of Bioinformatics & Computational Biology, University of Texas MD Anderson Cancer Center, Houston (L.T., P.L.L.). Division of Endocrinology, Metabolism Nutrition, Department of Medicine, Mayo Clinic, Rochester, Minnesota (C.A.M.).
      Abstract: Circulation Research, Ahead of Print.
      Background:Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated.Methods:Pressure overload was triggered by transverse aortic constriction in mice. Transcriptomic and metabolomic regulations were evaluated by RNA-sequencing and metabolomics, respectively. Stable isotope tracer labeling experiments were conducted to determine metabolic flux in vitro. Neonatal rat ventricular myocytes and H9c2 cells were used to examine molecular mechanisms.Results:We show that production of cardiomyocyte NADPH, a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with fibrosis and cardiomyopathy. We report that the pentose phosphate pathway and mitochondrial serine/glycine/folate metabolic signaling, 2 NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced by transverse aortic constriction. We identify ATF4 (activating transcription factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these 2 pathways. Consistently, joint pathway analysis of transcriptomic and metabolomic data reveals that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in neonatal rat ventricular myocytes increases NADPH-producing enzymes whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression augments metabolic flux within these 2 pathways. In vivo, cardiomyocyte specific deletion of ATF4 exacerbates cardiomyopathy in the setting of transverse aortic constriction and accelerates heart failure development, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes.Conclusions:Our findings reveal that ATF4 plays a critical role in the heart under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.
      Citation: Circulation Research
      PubDate: 2022-05-16T09:01:39Z
      DOI: 10.1161/CIRCRESAHA.122.321050
       
  • Tubular IL-1β Induces Salt Sensitivity in Diabetes by Activating
           Renal Macrophages

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      Authors: Luciana C. Veiras Ellen A. Bernstein DuoYao Cao Derick Okwan-Duodu Zakir Khan David R. Gibb Arantxa Roach Rachel Skelton Ryan M. Williams Kenneth E. Bernstein Jorge F. Giani Department of Biomedical Sciences; Cedars-Sinai Medical Center, Los Angeles, CA. (L.C.V., E.A.B., D.C., Z.K., K.E.B., J.F.G.) Department of Pathology Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA. (Z.K., D.R.G., K.E.B., J.F.G.) Department of Pathology, Stanford University, Palo Alto, CA (D.O.-D.). Department of Biomedical Engineering, The City College of New York (A.R., R.S., R.M.W.).
      Abstract: Circulation Research, Ahead of Print.
      Background:Chronic renal inflammation has been widely recognized as a major promoter of several forms of high blood pressure including salt-sensitive hypertension. In diabetes, IL (interleukin)-6 induces salt sensitivity through a dysregulation of the epithelial sodium channel. However, the origin of this inflammatory process and the molecular events that culminates with an abnormal regulation of epithelial sodium channel and salt sensitivity in diabetes are largely unknown.Methods and Results:Both in vitro and in vivo approaches were used to investigate the molecular and cellular contributors to the renal inflammation associated with diabetic kidney disease and how these inflammatory components interact to develop salt sensitivity in db/db mice. Thirty-four-week-old db/db mice display significantly higher levels of IL-1β in renal tubules compared with nondiabetic db/+ mice. Specific suppression of IL-1β in renal tubules prevented salt sensitivity in db/db mice. A primary culture of renal tubular epithelial cells from wild-type mice releases significant levels of IL-1β when exposed to a high glucose environment. Coculture of tubular epithelial cells and bone marrow-derived macrophages revealed that tubular epithelial cell-derived IL-1β promotes the polarization of macrophages towards a proinflammatory phenotype resulting in IL-6 secretion. To evaluate whether macrophages are the cellular target of IL-1β in vivo, diabetic db/db mice were transplanted with the bone marrow of IL-1 receptor type 1 knockout mice. db/db mice harboring an IL-1 receptor type 1 knockout bone marrow remained salt resistant, display lower renal inflammation and lower expression and activity of epithelial sodium channel compared with db/db transplanted with a wild-type bone marrow.Conclusions:Renal tubular epithelial cell-derived IL-1β polarizes renal macrophages towards a proinflammatory phenotype that promotes salt sensitivity through the accumulation of renal IL-6. When tubular IL-1β synthesis is suppressed or in db/db mice in which immune cells lack the IL-1R1, macrophage polarization is blunted resulting in no salt-sensitive hypertension.
      Citation: Circulation Research
      PubDate: 2022-05-16T09:00:02Z
      DOI: 10.1161/CIRCRESAHA.121.320239
       
  • Targeted Suppression of miRNA-33 Using pHLIP Improves Atherosclerosis
           Regression

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      Authors: Xinbo Zhang Noemi Rotllan Alberto Canfrán-Duque Jonathan Sun Jakub Toczek Anna Moshnikova Shipra Malik Nathan L. Price Elisa Araldi Wen Zhong Mehran M. Sadeghi Oleg A. Andreev Raman Bahal Yana K. Reshetnyak Yajaira Suárez Carlos Fernández-Hernando Vascular Biology; Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT. (J.T., M.M.S.) Section of Cardiology, Veterans Affairs Connecticut Healthcare System, West Haven (J.T., M.M.S.). Department of Physics, University of Rhode Island, Kingston (A.M., O.A.A., Y.K.R.). Department of Pharmaceutical Sciences, University of Connecticut, Storrs (S.M., R.B.).
      Abstract: Circulation Research, Ahead of Print.
      Background:miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis.Methods:We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics.Results:The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes (Col2a1,Col3a1,Col1a2,Fn1, etc) and tissue inhibitor of metalloproteinase 3 (Timp3) and downregulation ofMmp12in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33.Conclusions:This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.
      Citation: Circulation Research
      PubDate: 2022-05-10T04:01:14Z
      DOI: 10.1161/CIRCRESAHA.121.320296
       
  • Diversity in the Expressed Genomic Host Response to Myocardial Infarction

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      Authors: Augustin Toma Claudia dos Santos Beata Burzyńska Monika Góra Marek Kiliszek Natalie Stickle Holger Kirsten Leah Kosyakovsky Bo Wang Sean van Diepen Slava Epelman Yishay Szekely John C. Marshall Filio Billia Patrick R. Lawler Peter Munk Cardiac Centre; Toronto General Hospital, Canada (A.T., B.W., S.E., Y.S., F.B., P.R.L.). Department of Medicine (A.T., C.d.S., B.W., S.E., Y.S., F.B., P.R.L.) Interdepartmental Division of Critical Care Medicine, University of Toronto, Canada. (C.d.S., J.C.M., P.R.L.) St Michael’s Hospital, Toronto, Canada (C.d.S., J.C.M.). Institute of Biochemistry Epidemiology, Universität Leipzig, Germany (H.K.). Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA (L.K.). Division of Cardiology, Department of Critical Care, Department of Medicine, University of Alberta, Edmonton, Canada (S.v.D.). Ted Rogers Centre for Heart Research, Toronto, Canada (S.E., F.B., P.R.L.).
      Abstract: Circulation Research, Ahead of Print.

      Citation: Circulation Research
      PubDate: 2022-05-10T04:00:01Z
      DOI: 10.1161/CIRCRESAHA.121.318391
       
  • proANP Metabolism Provides New Insights Into Sacubitril/Valsartan Mode of
           Action

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      Authors: Thibault Michel Hélène Nougué Jérôme Cartailler Guillaume Lefèvre Malha Sadoune François Picard Alain Cohen-Solal Damien Logeart Jean-Marie Launay Nicolas Vodovar Inserm UMR-S 942; Université Paris Cité, France (T.M., H.N., J.C., M.S., A.C.-S., D.L., J.-M.L., N.V.). Department of Anaesthesiology Intensive Care Unit, Hôpital Lariboisière, Paris, France (H.N., J.C.). AP-HP, Hôpital Tenon, Biochemistry Department, Sorbonne Université, Paris, France (G.L.). Heart Failure Unit, Haut-Lévêque Hospital, Pessac, France (F.P.). Department of Cardiology, Lariboisière Hospital, Paris, France (A.C.-S., D.L.).
      Abstract: Circulation Research, Ahead of Print.
      BACKGROUND:Sacubitril/valsartan (S/V) treatment is associated with clinical benefits in patients with heart failure with reduced ejection fraction (HFrEF), but its mode of action remains elusive, although it involves the increase of ANP (atrial natriuretic peptide).METHODS AND RESULTS:Using a cohort of 73 HFrEF patients treated with S/V and controls, we deciphered the proteolytic cascade that converts proANP into 4 vasoactive peptides, including ANP, which exert vasodilatory actions. We found that proANP processing is sequential and involved meprin B, ECE (endothelin-converting enzyme) 1, and ANPEP (aminopeptidase N). This processing is limited in HFrEF patients when compared with controls via the downregulation of proANP production, corin, and meprin B activities by miR-425 and miR1-3p, resulting in limited production of proANP-derived bioactive peptides. S/V restored or compensated proANP processing by downregulating miR-425 and miR1-3p beyond levels observed in controls, hence increasing levels of proANP-derived bioactive peptides and vasodilation. In contrast, S/V directly and indirectly partially inhibited ECE1 and ANPEP. Consequently, ECE1 partial inhibition resulted in a lower-than-expected increase in ET1 (endothelin 1), tilting the vasoactive balance toward vasodilation, possibly explaining the hypotensive action of S/V. Finally, we show that proANP glycosylation interferes with the midregional proANP assay—a clinical surrogate for proANP production, preventing any pathophysiological interpretation of the results. Finally, the analysis of S/V dose escalation with respect to baseline treatments suggests S/V-specific effects.CONCLUSIONS:These findings offer mechanistic evidence to the natriuretic peptide–defective state in HFrEF, which is improved by S/V. These data also strongly suggest that S/V increases plasma ANP by multiple mechanisms that involve the indirect regulation of 2 microRNAs, besides its protection from NEP (neprilysin) cleavage. Altogether, these data provide new insights on HFrEF pathophysiology and the mode of action of S/V.
      Citation: Circulation Research
      PubDate: 2022-04-29T09:00:26Z
      DOI: 10.1161/CIRCRESAHA.122.320882
       
  • MFN2 Prevents Neointimal Hyperplasia in Vein Grafts via Destabilizing PFK1

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      Authors: Yuanjun Tang Yiting Jia Linwei Fan Han Liu Yuan Zhou Miao Wang Yuefeng Liu Juanjuan Zhu Wei Pang Jing Zhou Department of Physiology; Peking Union Medical College, Beijing, China. (M.W.)
      Abstract: Circulation Research, Ahead of Print.
      BACKGROUND:Mechanical forces play crucial roles in neointimal hyperplasia after vein grafting; yet, our understanding of their influences on vascular smooth muscle cell (VSMC) activation remains rudimentary.METHODS:A cuff mouse model was used to study vein graft hyperplasia. Fifteen percent to 1 Hz uniaxial cyclic stretch (arterial strain), 5% to 1 Hz uniaxial cyclic stretch or a static condition (venous strain) were applied to the cultured VSMCs. Metabolomics analysis, cell proliferation and migration assays, immunoblotting, co-immunoprecipitation, mutagenesis, pull-down and surface plasmon resonance assays were employed to elucidate the potential molecular mechanisms.RESULTS:RNA-sequencing in vein grafts and the controls identified changes in metabolic pathways and downregulation of mitochondrial protein MFN2 (mitofusin 2) in the vein grafts. Exposure of VSMCs to 15% stretch resulted in MFN2 downregulation, mitochondrial fragmentation, metabolic shift from mitochondrial oxidative phosphorylation to glycolysis, and cell proliferation and migration, as compared with that to a static condition or 5% stretch. Metabolomics analysis indicated an increased generation of fructose 1,6-bisphosphate, an intermediate in the glycolytic pathway converted by PFK1 (phosphofructokinase 1) from fructose-6-phosphate, in cells exposed to 15% stretch. Mechanistic study revealed that MFN2 physically interacts through its C-terminus with PFK1. MFN2 knockdown or exposure of cells to 15% stretch promoted stabilization of PFK1, likely through interfering the association between PFK1 and the E3 ubiquitin ligase TRIM21 (E3 ubiquitin ligase tripartite motif [TRIM]-containing protein 21), thus, decreasing the ubiquitin-protease-dependent PFK1 degradation. In addition, study of mechanotransduction utilizing pharmaceutical inhibition indicated that the MFN2 downregulation by 15% stretch was dependent on inactivation of the SP1 (specificity protein 1) and activation of the JNK (c-Jun N-terminal kinase) and ROCK (Rho-associated protein kinase). Adenovirus-mediated MFN2 overexpression or pharmaceutical inhibition of PFK1 suppressed the 15% stretch-induced VSMC proliferation and migration and alleviated neointimal hyperplasia in vein grafts.CONCLUSIONS:MFN2 is a mechanoresponsive protein that interacts with PFK1 to mediate PFK1 degradation and therefore suppresses glycolysis in VSMCs.
      Citation: Circulation Research
      PubDate: 2022-04-22T09:00:03Z
      DOI: 10.1161/CIRCRESAHA.122.320846
       
  • Tenascin-X Mediates Flow-Induced Suppression of EndMT and Atherosclerosis

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      Authors: Guozheng Liang ShengPeng Wang Jingchen Shao YoungJune Jin Liran Xu Yang Yan Stefan Günther Lei Wang Stefan Offermanns Department of Pharmacology; Max Planck Institute for Heart Bad Nauheim, Germany (S.O.).
      Abstract: Circulation Research, Ahead of Print.
      Background:Endothelial-to-mesenchymal transition (EndMT) has been identified as a critical driver of vascular inflammation and atherosclerosis, and TGF-β (transforming growth factor β) is a key mediator of EndMT. Both EndMT and atherosclerosis are promoted by disturbed flow, whereas unidirectional laminar flow limits EndMT and is atheroprotective. How EndMT and endothelial TGF-β signaling are regulated by different flow patterns is, however, still poorly understood.Methods:Flow chamber experiments in vitro and endothelium-specific knockout mice were used to study the role of tenascin-X in the regulation of EndMT and atherosclerosis as well as the underlying mechanisms.Results:In human endothelial cells as well as in human and mouse aortae, unidirectional laminar flow but not disturbed flow strongly increased endothelial expression of the extracellular matrix protein TN-X (tenascin-X) in a KLF4 (Krüppel-like factor 4) dependent manner. Mice with endothelium-specific loss of TN-X (EC-Tnxb-KO) showed increased endothelial TGF-β signaling as well as increased endothelial expression of EndMT and inflammatory marker genes. When EC-Tnxb-KO mice were subjected to partial carotid artery ligation, we observed increased vascular remodeling. EC-Tnxb-KO mice crossed to low-density lipoprotein receptor-deficient mice showed advanced atherosclerotic lesions after being fed a high-fat diet. Treatment of EC-Tnxb-KO mice with an anti-TGF-beta antibody or additional endothelial loss of TGF-beta receptors 1 and 2 normalized endothelial TGF-beta signaling and prevented EndMT. In in vitro studies, we found that TN-X through its fibrinogen-like domain directly interacts with TGF-β and thereby interferes with its binding to the TGF-β receptor.Conclusions:In summary, we show that TN-X is a central mediator of flow-induced inhibition of EndMT, endothelial inflammation and atherogenesis, which functions by binding to and by blocking the activity of TGF-β. Our data identify a novel mechanism of flow-dependent regulation of vascular TGF-β, which holds promise for generating new strategies to prevent vascular inflammation and atherosclerosis.
      Citation: Circulation Research
      PubDate: 2022-04-21T09:00:02Z
      DOI: 10.1161/CIRCRESAHA.121.320694
       
  • Genetic Lineage Tracing of Pericardial Cavity Macrophages in the Injured
           Heart

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      Authors: Hengwei Jin Kuo Liu Xiuzhen Huang Huanhuan Huo Jialing Mou Zengyong Qiao Ben He Bin Zhou State Key Laboratory of Cell Biology; Shanghai Institute of Biochemistry Technology, ShanghaiTech University, China (B.Z.).
      Abstract: Circulation Research, Ahead of Print.
      Background:Macrophages play an important role in cardiac repair after myocardial infarction (MI). In addition to the resident macrophages and blood-derived monocytes, Gata6+cavity macrophages located in the pericardial space were recently reported to relocate to the injured myocardium and prevent cardiac fibrosis. However, there is no direct genetic evidence to support it.Methods:We used dual recombinases (Cre and Dre) to specifically label Gata6+pericardial macrophages (GPCMs) in vivo. For functional study, we generated genetic systems to specifically ablate GPCMs by induced expression of diphtheria toxin receptor or knockout of Gata6 (GATA binding protein 6) gene in GPCMs. We used these genetic systems to study GPCMs in pericardium intact MI model.Results:Dual recombinases-mediated genetic system targeted GPCMs specifically and efficiently. Lineage tracing study revealed accumulation of GPCMs on the surface of MI heart without deep penetration into the myocardium. We did not detect significant change of cardiac fibrosis or function of MI hearts after cell ablation or Gata6 knockout in GPCMs.Conclusions:GPCMs minimally invade the injured heart after MI. Nor do they prevent cardiac fibrosis and exhibit reparative function on injured heart. This study also underlines the importance of using specific genetic tool for studying in vivo cell fates and functions.
      Citation: Circulation Research
      PubDate: 2022-04-20T09:01:07Z
      DOI: 10.1161/CIRCRESAHA.122.320567
       
  • Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T
           Cells

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      Authors: Rulin Zhuang Jingshu Chen Henry S. Cheng Carmel Assa Anurag Jamaiyar Arvind K. Pandey Daniel Pérez-Cremades Bofang Zhang Aspasia Tzani Akm Khyrul Wara Jorge Plutzky Victor Barrera Preetida Bhetariya Richard N. Mitchell Zhongmin Liu Mark W. Feinberg Department of Medicine; Cardiovascular Division, Brigham Women’s Hospital, Harvard Medical School, Boston, MA (R.N.M.).
      Abstract: Circulation Research, Ahead of Print.
      BACKGROUND:Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Ang II (angiotensin II) contributes to vascular disease and end-organ damage via promoting T-cell activation. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood.METHODS:TF (transcription factor) profiling was performed in peripheral blood mononuclear cells of hypertensive patients. CD4-targeted KLF10 (Kruppel like factor 10)-deficient (Klf10fl/flCD4Cre+; [TKO]) and CD4-Cre (Klf10+/+CD4Cre+; (Cre)) control mice were subjected to Ang II infusion. End point characterization included cardiac echocardiography, aortic imaging, multiorgan histology, flow cytometry, cytokine analysis, aorta and fibroblast transcriptomic analysis, and aortic single-cell RNA-sequencing.RESULTS:TF profiling identified increasedKLF10expression in hypertensive human subjects and in CD4+ T cells in Ang II-treated mice. TKO mice showed enhanced perivascular fibrosis, but not interstitial fibrosis, in aorta, heart, and kidney in response to Ang II, accompanied by alterations in global longitudinal strain, arterial stiffness, and kidney function compared with Cre control mice. However, blood pressure was unchanged between the 2 groups. Mechanistically, KLF10 bound to the IL (interleukin)-9 promoter and interacted with HDAC1 (histone deacetylase 1) inhibit IL-9 transcription. Increased IL-9 in TKO mice induced fibroblast intracellular calcium mobilization, fibroblast activation, and differentiation and increased production of collagen and extracellular matrix, thereby promoting the progression of perivascular fibrosis and impairing target organ function. Remarkably, injection of anti-IL9 antibodies reversed perivascular fibrosis in Ang II-infused TKO mice and C57BL/6 mice. Single-cell RNA-sequencing revealed fibroblast heterogeneity with activated signatures associated with robust ECM (extracellular matrix) and perivascular fibrosis in Ang II-treated TKO mice.CONCLUSIONS:CD4+ T cell deficiency ofKlf10exacerbated perivascular fibrosis and multi-organ dysfunction in response to Ang II via upregulation of IL-9.Klf10or IL-9 in T cells might represent novel therapeutic targets for treatment of vascular or fibrotic diseases.
      Citation: Circulation Research
      PubDate: 2022-04-20T09:00:02Z
      DOI: 10.1161/CIRCRESAHA.121.320420
       
  • Small Extracellular Vesicles From Brown Adipose Tissue Mediate Exercise
           Cardioprotection

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      Authors: Hang Zhao Xiyao Chen Guangyu Hu Congye Li Lanyan Guo Ling Zhang Fangfang Sun Yunlong Xia Wenjun Yan Ze Cui Yongzhen Guo Xiong Guo Chong Huang Miaomiao Fan Shan Wang Fuyang Zhang Ling Tao Department of Cardiology; The Fourth Military Medical University, Xi’an, China. (H.Z., X.C., G.H., C.L., L.G., L.Z., F.S., Y.X., W.Y., Z.C., Y.G., X.G., C.H., M.F., S.W., F.Z., L.T.) Department of Geriatrics, The Fourth Military Medical University, Xi’an, China. (X.C.) Xijing Hospital Department of Toxicology, School of Public Health, The Fourth Military Medical University, Xi’an, China. (Y.G.) Department of Pharmacy, the 960th Hospital of the Logistics Support Force, Jinan, China (H.Z.).
      First page: 1490
      Abstract: Circulation Research, Ahead of Print.
      Rationale:Long-term exercise provides reliable cardioprotection via mechanisms still incompletely understood. Although traditionally considered a thermogenic tissue, brown adipose tissue (BAT) communicates with remote organs (eg, the heart) through its endocrine function. BAT expands in response to exercise, but its involvement in exercise cardioprotection remains undefined.Objective:This study investigated whether small extracellular vesicles (sEVs) secreted by BAT and their contained microRNAs (miRNAs) regulate cardiomyocyte survival and participate in exercise cardioprotection in the context of myocardial ischemia/reperfusion (MI/R) injury.Methods and Results:Four weeks of exercise resulted in a significant BAT expansion in mice. Surgical BAT ablation before MI/R weakened the salutary effects of exercise. Adeno-associated virus 9 vectors carrying short hairpin RNA targetingRab27a(a GTPase required for sEV secretion) or control viruses were injected in situ into the interscapular BAT. Exercise-mediated protection against MI/R injury was greatly attenuated in mice whose BAT sEV secretion was suppressed byRab27asilencing. Intramyocardial injection of the BAT sEVs ameliorated MI/R injury, revealing the cardioprotective potential of BAT sEVs. Discovery-driven experiments identified miR-125b-5p, miR-128-3p, and miR-30d-5p (referred to as the BAT miRNAs) as essential BAT sEV components for mediating cardioprotection. BAT-specific inhibition of the BAT miRNAs prevented their upregulation in plasma sEVs and hearts of exercised mice and attenuated exercise cardioprotection. Mechanistically, the BAT miRNAs cooperatively suppressed the proapoptotic MAPK (mitogen-associated protein kinase) pathway by targeting a series of molecules (eg,Map3k5,Map2k7, andMap2k4) in the signaling cascade. Delivery of BAT sEVs into hearts or cardiomyocytes suppressed MI/R-related MAPK pathway activation, an effect that disappeared with the combined use of the BAT miRNA inhibitors.Conclusions:The sEVs secreted by BAT participate in exercise cardioprotection via delivering the cardioprotective miRNAs into the heart. These results provide novel insights into the mechanisms underlying the BAT-cardiomyocyte interaction and highlight BAT sEVs and their contained miRNAs as alternative candidates for exercise cardioprotection.
      Citation: Circulation Research
      PubDate: 2022-04-07T09:00:02Z
      DOI: 10.1161/CIRCRESAHA.121.320458
       
  • Human Coronary Plaque T Cells Are Clonal and Cross-React to Virus and Self

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      Authors: Roshni Roy Chowdhury Jessica D’Addabbo Xianxi Huang Stefan Veizades Koki Sasagawa David M. Louis Paul Cheng Jan Sokol Annie Jensen Alexandria Tso Vishnu Shankar Ben Shogo Wendel Isaac Bakerman Grace Liang Tiffany Koyano Robyn Fong Allison Nau Herra Ahmad J.K. Gopakumar Robert Wirka Andrew Lee Jack Boyd Y. Joseph Woo Thomas Quertermous Gunsagar Gulati Siddhartha Jaiswal Yueh-Hsiu Chien Charles Chan Mark M. Davis Patricia K. Nguyen Department of Microbiology; Regenerative Medicine, Stanford University, CA. (G.G., C.C.) Howard Hughes Medical Institute, Stanford University, CA. (M.M.D.) Department of Medicine, Section of Genetic Medicine, University of Chicago, IL (R.R.C.). First Affiliated Hospital of Shantou University Medical College, Guangdong, China (X.H.). Edinburgh Medical School, United Kingdom (S.V., D.M.L., M.M.D.). Institute for Cancer Research, Shenzhen Bay Laboratory, China (A.L.).
      First page: 1510
      Abstract: Circulation Research, Ahead of Print.
      Background:Once considered primarily a disorder of lipid deposition, coronary artery disease is an incurable, life-threatening disease that is now also characterized by chronic inflammation notable for the buildup of atherosclerotic plaques containing immune cells in various states of activation and differentiation. Understanding how these immune cells contribute to disease progression may lead to the development of novel therapeutic strategies.Methods:We used single-cell technology and in vitro assays to interrogate the immune microenvironment of human coronary atherosclerotic plaque at different stages of maturity.Results:In addition to macrophages, we found a high proportion of αβ T cells in the coronary plaques. Most of these T cells lack high expression ofCCR7andL-selectin, indicating that they are primarily antigen-experienced, memory cells. Notably, nearly one-third of these cells express theHLA-DRAsurface marker, signifying activation through their TCRs (T-cell receptors). Consistent with this, TCR repertoire analysis confirmed the presence of activated αβ T cells (CD4<CD8), exhibiting clonal expansion of specific TCRs. Interestingly, we found that these plaque T cells had TCRs specific for influenza, coronavirus, and other viral epitopes, which share sequence homologies to proteins found on smooth muscle cells and endothelial cells, suggesting potential autoimmune-mediated T-cell activation in the absence of active infection. To better understand the potential function of these activated plaque T cells, we then interrogated their transcriptome at the single-cell level. Of the 3 T-cell phenotypic clusters with the highest expression of the activation markerHLA-DRAidentified by the Seurat algorithm, 2 clusters express a proinflammatory and cytolytic signature characteristic of CD8 cells, while the other expresses AREG (amphiregulin), which promotes smooth muscle cell proliferation and fibrosis, and, thus, contributes to plaque progression.Conclusions:Taken together, these findings demonstrate that plaque T cells are clonally expanded potentially by antigen engagement, are potentially reactive to self-epitopes, and may interact with smooth muscle cells and macrophages in the plaque microenvironment.
      Citation: Circulation Research
      PubDate: 2022-04-18T09:00:14Z
      DOI: 10.1161/CIRCRESAHA.121.320090
       
  • Piezo1 Is a Mechanosensor Channel in Central Nervous System Capillaries

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      Authors: Osama F. Harraz Nicholas R. Klug Amanda J. Senatore David C. Hill-Eubanks Mark T. Nelson Department of Pharmacology; Larner College of Medicine, University of Vermont, Burlington. (O.F.H., N.R.K., A.J.S., D.C.H.-E., M.T.N.) Vermont Center for Cardiovascular Brain Health, University of Vermont, Burlington. (O.F.H., M.T.N.) Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, United Kingdom. (M.T.N.) Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance NHS Group, University of Manchester, United Kingdom. (M.T.N.)
      First page: 1531
      Abstract: Circulation Research, Ahead of Print.
      Capillaries are equipped to sense neurovascular coupling agents released onto the outer wall of a capillary, translating these external signals into electrical/Ca2+changes that play a crucial role in blood flow regulation and ensuring that neuronal demands are met. However, control mechanisms attributable to forces imposed onto the lumen are less clear. Here, we show that Piezo1 channels act as mechanosensors in central nervous system capillaries. Electrophysiological analyses confirmed expression and function of Piezo1 channels in brain cortical and retinal capillaries. Activation of Piezo1 channels evoked currents that were sensitive to endothelial cell–specific Piezo1 deletion. Using genetically encoded Ca2+indicator mice and an ex vivo pressurized retina preparation, we found that activation of Piezo1 channels by mechanical forces triggered Ca2+signals in capillary endothelial cells. Collectively, these findings indicate that Piezo1 channels are capillary mechanosensors that initiate crucial Ca2+signals and could, therefore, have a profound impact on central nervous system blood flow control.
      Citation: Circulation Research
      PubDate: 2022-04-06T09:00:02Z
      DOI: 10.1161/CIRCRESAHA.122.320827
       
  • The IFNγ-PDL1 Pathway Enhances CD8T-DCT Interaction to Promote
           Hypertension

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      Authors: Lance N. Benson Yunmeng Liu Xiangting Wang Yunzhao Xiong Sung W. Rhee Yunping Guo Katherine S. Deck Christoph J. Mora Lin-Xi Li Lu Huang J. Tucker Andrews Zhiqiang Qin Robert S. Hoover Benjamin Ko Ryan M. Williams Daniel A. Heller Edgar A. Jaimes Shengyu Mu Department of Pharmacology; Immunology, University of Arkansas for Medical Sciences. (L.-X.L., L.H., J.T.A.) Department of Pathology, University of Arkansas for Medical Sciences. (Z.Q.) Department of Medicine, Tulane University School of Medicine, New Orleans, LA (R.S.H.) Now with Department of Internal Medicine, Hebei University of Chinese Medicine, Shijiazhuang, He-Bei, China (Y.L., X.W.). Department of Medicine, University of Chicago, IL (B.K.). Department of Biomedical Engineering, The City College of New York (R.M.W.). Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center (D.A.H.). Department of Medicine, Memorial Sloan Kettering Cancer Center, NY (E.A.J.).
      First page: 1550
      Abstract: Circulation Research, Ahead of Print.
      Background:Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to increase sodium chloride co-transporter expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated.Methods:We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8+T cells (CD8T) from hypertensive animals to normotensive animals in in-vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in-vitro model to test the effect of CD8T activation in promoting sodium chloride co-transporter-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. IFNγ (interferon γ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in-vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis.Results:We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of sodium chloride co-transporter in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models.Conclusions:Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFN-γ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.
      Citation: Circulation Research
      PubDate: 2022-04-18T09:00:02Z
      DOI: 10.1161/CIRCRESAHA.121.320373
       
  • Epigenetic Upregulation of H19 and AMPK Inhibition Concurrently Contribute
           to S-Adenosylhomocysteine Hydrolase Deficiency-Promoted Atherosclerotic
           Calcification

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      Authors: Xin Dai Si Liu Lokyu Cheng Ting Huang Honghui Guo Dongliang Wang Min Xia Wenhua Ling Yunjun Xiao Guangdong Provincial Key Laboratory of Digestive Cancer Research; The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.D., S.L., L.C., T.H., Y.X.). Department of Nutrition, School of Public Health, Guangdong Medical University, Dongguan, China (H.G.). Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition Health, School of Public Health, Sun Yat-sen University, Guangzhou, China (D.W., M.X., W.L.).
      First page: 1565
      Abstract: Circulation Research, Ahead of Print.
      Background:S-adenosylhomocysteine (SAH) is a risk factor of cardiovascular disease; inhibition of SAH hydrolase (SAHH) results in SAH accumulation and induces endothelial dysfunction and atherosclerosis. However, the effect and mechanism of SAHH in atherosclerotic calcification is still unclear. We aimed to explore the role and mechanism of SAHH in atherosclerotic calcification.Methods:The relationship between SAHH and atherosclerotic calcification was investigated in patients with coronary atherosclerotic calcification. Different in vivo genetic models were used to examine the effect of SAHH deficiency on atherosclerotic calcification. Human aortic and murine vascular smooth muscle cells (VSMCs) were cultured to explore the underlying mechanism of SAHH on osteoblastic differentiation of VSMCs.Results:The expression and activity of SAHH were decreased in calcified human coronary arteries and inversely associated with coronary atherosclerotic calcification severity, whereas plasma SAH and total homocysteine levels were positively associated with coronary atherosclerotic calcification severity. Heterozygote knockout of SAHH promoted atherosclerotic calcification. Specifically, VSMC-deficient but not endothelial cell–deficient or macrophage-deficient SAHH promoted atherosclerotic calcification. Mechanistically, SAHH deficiency accumulated SAH levels and induced H19-mediated Runx2 (runt-related transcription factor 2)-dependent osteoblastic differentiation of VSMCs by inhibiting DNMT3b (DNA methyltransferase 3 beta) and leading to hypomethylation of the H19 promoter. On the other hand, SAHH deficiency resulted in lower intracellular levels of adenosine and reduced AMPK (AMP-activated protein kinase) activation. Adenosine supplementation activated AMPK and abolished SAHH deficiency–induced expression of H19 and Runx2 and osteoblastic differentiation of VSMCs. Finally, AMPK activation by adenosine inhibited H19 expression by inducing Sirt1-mediated histone H3 hypoacetylation and DNMT3b-mediated hypermethylation of the H19 promoter in SAHH deficiency VSMCs.Conclusions:We have confirmed a novel correlation between SAHH deficiency and atherosclerotic calcification and clarified a new mechanism that epigenetic upregulation of H19 and AMPK inhibition concurrently contribute to SAHH deficiency–promoted Runx2-dependent atherosclerotic calcification.
      Citation: Circulation Research
      PubDate: 2022-04-12T09:00:06Z
      DOI: 10.1161/CIRCRESAHA.121.320251
       
  • The E3 Ligase TRIM16 Is a Key Suppressor of Pathological Cardiac
           Hypertrophy

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      Authors: Jiayi Liu Wei Li Ke-Qiong Deng Song Tian Hui Liu Hongjie Shi Qian Fang Zhen Liu Ze Chen Tian Tian Shanyu Gan Fengjiao Hu Manli Hu Xu Cheng Yan-Xiao Ji Peng Zhang Zhi-Gang She Xiao-Jing Zhang Shaoze Chen Jingjing Cai Hongliang Li Department of Cardiology; Renmin Hospital of Wuhan University, Wuhan, China (J.L., W.L., T.T., Z.-G.S., H.L.). Institute of Model Animal of Wuhan University, China (J.L., W.L., K.-Q.D., S.T., H. Liu, H.S., Q.F., Z.L., Z.C., T.T., S.G., F.H., M.H., X.C., Y.-X.J., P.Z., Z.-G.S., X.-J.Z., H. Li). Department of Cardiology, Zhongnan Hospital of Wuhan University, China. (K.-Q.D., Z.C.) Medical Science Research Center, Zhongnan Hospital of Wuhan University, China. (F.H., H. Li) Gannan Innovation Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou, China. (H. Liu, M.H., X.C.) School of Basic Medical Sciences, Wuhan University, China (H.S., S.G., Y.-X.J., P.Z., X.-J.Z., H. Li). Department of Cardiology, Huanggang Central Hospital, China (S.C.). Huanggang Institute of Translational Medicine, Huanggang, China (S.C.). Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China (J.C.).
      First page: 1586
      Abstract: Circulation Research, Ahead of Print.
      Background:Pathological cardiac hypertrophy is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase TRIM16 (tripartite motif–containing protein 16) has been recognized as a pivotal regulator to control cell survival, immune response, and oxidative stress. However, the role of Trim16 in cardiac hypertrophy is unknown.Methods:We generated cardiac-specific knockout mice and adeno-associated virus serotype 9–Trim16 mice to evaluate the function of Trim16 in pathological myocardial hypertrophy. The direct effect of TRIM16 on cardiomyocyte enlargement was examined using an adenovirus system. Furthermore, we combined RNA-sequencing and interactome analysis that was followed by multiple molecular biological methodologies to identify the direct target and corresponding molecular events contributing to TRIM16 function.Results:We found an intimate correlation of Trim16 expression with hypertrophy-related heart failure in both human and mouse. Our functional investigations and unbiased transcriptomic analyses clearly demonstrated that Trim16 deficiency markedly exacerbated cardiomyocyte enlargement in vitro and in transverse aortic constriction–induced cardiac hypertrophy mouse model, whereas Trim16 overexpression attenuated cardiac hypertrophy and remodeling. Mechanistically, Prdx1 (peroxiredoxin 1) is an essential target of Trim16 in cardiac hypertrophy. We found that Trim16 interacts with Prdx1 and inhibits its phosphorylation, leading to a robust enhancement of its downstream Nrf2 (nuclear factor–erythroid 2–related factor 2) pathway to block cardiac hypertrophy. Trim16-blocked Prdx1 phosphorylation was largely dependent on a direct interaction between Trim16 and Src and the resultant Src ubiquitinational degradation. Notably, Prdx1 knockdown largely abolished the anti-hypertrophic effects of Trim16 overexpression.Conclusions:Our findings provide the first evidence supporting Trim16 as a novel suppressor of pathological cardiac hypertrophy and indicate that targeting the Trim16-Prdx1 axis represents a promising therapeutic strategy for hypertrophy-related heart failure.
      Citation: Circulation Research
      PubDate: 2022-04-19T09:00:03Z
      DOI: 10.1161/CIRCRESAHA.121.318866
       
 
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