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  • 1
    Online Resource
    Online Resource
    Coordination of endothelial cell positioning and fate specification by the epicardium
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-07-06)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-07-06)
    Abstract: The organization of an integrated coronary vasculature requires the specification of immature endothelial cells (ECs) into arterial and venous fates based on their localization within the heart. It remains unclear how spatial information controls EC identity and behavior. Here we use single-cell RNA sequencing at key developmental timepoints to interrogate cellular contributions to coronary vessel patterning and maturation. We perform transcriptional profiling to define a heterogenous population of epicardium-derived cells (EPDCs) that express unique chemokine signatures. We identify a population of Slit2+ EPDCs that emerge following epithelial-to-mesenchymal transition (EMT), which we term vascular guidepost cells. We show that the expression of guidepost-derived chemokines such as Slit2 are induced in epicardial cells undergoing EMT, while mesothelium-derived chemokines are silenced. We demonstrate that epicardium-specific deletion of myocardin-related transcription factors in mouse embryos disrupts the expression of key guidance cues and alters EPDC-EC signaling, leading to the persistence of an immature angiogenic EC identity and inappropriate accumulation of ECs on the epicardial surface. Our study suggests that EC pathfinding and fate specification is controlled by a common mechanism and guided by paracrine signaling from EPDCs linking epicardial EMT to EC localization and fate specification in the developing heart.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-24414-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2553671-0
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  • 2
    Online Resource
    Online Resource
    GRP1 Pleckstrin Homology Domain:  Activation Parameters and Novel Search Mechanism for Rare Target Lipid
    American Chemical Society (ACS) ; 2004
    In:  Biochemistry Vol. 43, No. 51 ( 2004-12-01), p. 16161-16173
    Details
    In: Biochemistry, American Chemical Society (ACS), Vol. 43, No. 51 ( 2004-12-01), p. 16161-16173
    Type of Medium: Online Resource
    ISSN: 0006-2960 , 1520-4995
    URL: Article
    DOI: 10.1021/bi049017a
    RVK:
    WA 15000
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2004
    detail.hit.zdb_id: 1472258-6
    SSG: 12
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  • 3
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    Mechanosensitive Gene Regulation by Myocardin-Related Transcription Factors Is Required for Cardiomyocyte Integrity in Load-Induced Ventricular Hypertrophy
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Vol. 138, No. 17 ( 2018-10-23), p. 1864-1878
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 138, No. 17 ( 2018-10-23), p. 1864-1878
    Abstract: Hypertrophic cardiomyocyte growth and dysfunction accompany various forms of heart disease. The mechanisms responsible for transcriptional changes that affect cardiac physiology and the transition to heart failure are not well understood. The intercalated disc (ID) is a specialized intercellular junction coupling cardiomyocyte force transmission and propagation of electrical activity. The ID is gaining attention as a mechanosensitive signaling hub and hotspot for causative mutations in cardiomyopathy. Methods: Transmission electron microscopy, confocal microscopy, and single-molecule localization microscopy were used to examine changes in ID structure and protein localization in the murine and human heart. We conducted detailed cardiac functional assessment and transcriptional profiling of mice lacking myocardin-related transcription factor (MRTF)-A and MRTF-B specifically in adult cardiomyocytes to evaluate the role of mechanosensitive regulation of gene expression in load-induced ventricular remodeling. Results: We found that MRTFs localize to IDs in the healthy human heart and accumulate in the nucleus in heart failure. Although mice lacking MRTFs in adult cardiomyocytes display normal cardiac physiology at baseline, pressure overload leads to rapid heart failure characterized by sarcomere disarray, ID disintegration, chamber dilation and wall thinning, cardiac functional decline, and partially penetrant acute lethality. Transcriptional profiling reveals a program of actin cytoskeleton and cardiomyocyte adhesion genes driven by MRTFs during pressure overload. Indeed, conspicuous remodeling of gap junctions at IDs identified by single-molecule localization microscopy may partially stem from a reduction in Mapre1 expression, which we show is a direct mechanosensitive MRTF target. Conclusions: Our study describes a novel paradigm in which MRTFs control an acute mechanosensitive signaling circuit that coordinates cross-talk between the actin and microtubule cytoskeleton and maintains ID integrity and cardiomyocyte homeostasis in heart disease.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.117.031788
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1466401-X
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  • 4
    Online Resource
    Online Resource
    Exercise promotes a cardioprotective gene program in resident cardiac fibroblasts
    American Society for Clinical Investigation ; 2019
    In:  JCI Insight Vol. 4, No. 1 ( 2019-1-10)
    Details
    In: JCI Insight, American Society for Clinical Investigation, Vol. 4, No. 1 ( 2019-1-10)
    Type of Medium: Online Resource
    ISSN: 2379-3708
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1172/jci.insight.92098
    DOI: 10.1172/jci.insight.92098DS1
    DOI: 10.1172/jci.insight.92098DS2
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2019
    detail.hit.zdb_id: 2874757-4
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  • 5
    Online Resource
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    Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 15 ( 2018-04-10)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 15 ( 2018-04-10)
    Abstract: Heart disease is associated with the accumulation of resident cardiac fibroblasts (CFs) that secrete extracellular matrix (ECM), leading to the development of pathological fibrosis and heart failure. However, the mechanisms underlying resident CF proliferation remain poorly defined. Here, we report that small proline-rich protein 2b ( Sprr2b ) is among the most up-regulated genes in CFs during heart disease. We demonstrate that SPRR2B is a regulatory subunit of the USP7/MDM2-containing ubiquitination complex. SPRR2B stimulates the accumulation of MDM2 and the degradation of p53, thus facilitating the proliferation of pathological CFs. Furthermore, SPRR2B phosphorylation by nonreceptor tyrosine kinases in response to TGF-β1 signaling and free-radical production potentiates SPRR2B activity and cell cycle progression. Knockdown of the Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates USP7/MDM2 binding and p53 degradation, leading to CF cell cycle arrest. Importantly, SPRR2B expression is elevated in cardiac tissue from human heart failure patients and correlates with the proliferative state of patient-derived CFs in a process that is reversed by insulin growth factor-1 signaling. These data establish SPRR2B as a unique component of the USP7/MDM2 ubiquitination complex that drives p53 degradation, CF accumulation, and the development of pathological cardiac fibrosis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1717423115
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
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    Abstract 108: Exercise Promotes a Cardioprotective Gene Program in Resident Cardiac Fibroblasts
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Circulation Research Vol. 121, No. suppl_1 ( 2017-07-21)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 121, No. suppl_1 ( 2017-07-21)
    Abstract: Exercise and disease both induce hypertrophic cardiac growth, but only disease results in fibrosis and compromised heart function. Transcriptional profiling of resident cardiac fibroblasts (CFs), the primary cellular source of fibrosis, was used to define the gene expression programs (GEP) underlying this divergent functional outcome. Bioinformatic analyses revealed distinct transcriptional responses to exercise and disease, including induction of Rho- and SRF-dependent remodeling genes in disease and NRF2-dependent antioxidant genes in exercise. The expression of a number of antioxidant genes, including metallothioneins (Mt1 and Mt2), are specifically maintained in CFs after exercise and lost in disease. Mice lacking Mt1/2 show signs of cardiac dysfunction after exercise, including cardiac fibrosis, vascular rarefaction, and reduced heart function. Importantly, Mt levels are also reduced in human heart failure (HF) patients, suggesting a potentially conserved cardioprotective role in humans. Non-canonical TGF-β1-mediated p38-MAPK signaling has previously been implicated in HF, therefore we tested the role of p38 signaling in Mt regulation. Pharmacological inhibition of p38 in human HF fibroblasts restores Mt1 and Mt2 expression and blunts the pathological fibroblast phenotype. Taken together, our study defines the transcriptional response of CFs to exercise and disease and reveals a cardioprotective mechanism that is lost in disease.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.121.suppl_1.108
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1467838-X
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  • 7
    Online Resource
    Online Resource
    Prevention of Fibrosis and Pathological Cardiac Remodeling by Salinomycin
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation Research Vol. 128, No. 11 ( 2021-05-28), p. 1663-1678
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 128, No. 11 ( 2021-05-28), p. 1663-1678
    Abstract: Cardiomyopathy is characterized by the deposition of extracellular matrix by activated resident cardiac fibroblasts called myofibroblasts. There are currently no therapeutic approaches to blunt the development of pathological fibrosis and ventricle chamber stiffening that ultimately leads to heart failure. Objective: We undertook a high-throughput screen to identify small molecule inhibitors of myofibroblast activation that might limit the progression of heart failure. We evaluated the therapeutic efficacy of the polyether ionophore salinomycin in patient-derived cardiac fibroblasts and preclinical mouse models of ischemic and nonischemic heart failure. Methods and Results: Here, we demonstrate that salinomycin displays potent anti-fibrotic activity in cardiac fibroblasts obtained from heart failure patients. In preclinical studies, salinomycin prevents cardiac fibrosis and functional decline in mouse models of ischemic and nonischemic heart disease. Remarkably, interventional treatment with salinomycin attenuates preestablished pathological cardiac remodeling secondary to hypertension and limits scar expansion when administered after a severe myocardial infarction. Mechanistically, salinomycin inhibits cardiac fibroblast activation by preventing p38/MAPK (mitogen activated protein kinase) and Rho signaling. Salinomycin also promotes cardiomyocyte survival and improves coronary vessel density, suggesting that cardioprotection conferred by salinomycin occurs via the integration of multiple mechanisms in multiple relevant cardiac cell types. Conclusions: These data establish salinomycin as an antifibrotic agent that targets multiple cardioprotection pathways, thereby holding promise for the treatment of heart failure patients.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.120.317791
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 1467838-X
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  • 8
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    Online Resource
    Pre-existing fibroblasts of epicardial origin are the primary source of pathological fibrosis in cardiac ischemia and aging
    Elsevier BV ; 2019
    In:  Journal of Molecular and Cellular Cardiology Vol. 129 ( 2019-04), p. 92-104
    Details
    In: Journal of Molecular and Cellular Cardiology, Elsevier BV, Vol. 129 ( 2019-04), p. 92-104
    Type of Medium: Online Resource
    ISSN: 0022-2828
    URL: Article
    DOI: 10.1016/j.yjmcc.2019.01.015
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 1469767-1
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  • 9
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    Abstract 511: Regulation of p53 Protein Levels Drives Activation of Cardiac Fibroblasts in Response to Pressure Overload
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Circulation Research Vol. 125, No. Suppl_1 ( 2019-08-02)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 125, No. Suppl_1 ( 2019-08-02)
    Abstract: Heart disease is accompanied by the accumulation of resident cardiac fibroblasts (CF) that subsequently become myofibroblasts and secrete copious amounts of extracellular matrix (ECM), impeding cardiac function and driving the progression of heart failure. Understanding the mechanisms coordinating CF accumulation and myofibroblast activation may reveal novel therapeutic strategies to block pathologic fibrosis. We recently found that s mall pr oline r ich protein 2b (SPRR2B) drives CF proliferation in response to pathological cues by facilitating MDM2-dependent proteasomal degradation of p53. Surprisingly, although Sprr2b gene deletion or targeted mutation of the USP7/MDM2 interacting domain in mice ( Sprr2b-KO and Sprr2b-USP m , respectively) stimulated the expression of p53-dependent cell cycle arrest genes, mutant animals also developed excessive fibrosis in LV pressure overload. The development of fibrosis in Sprr2b mutant mice was traced primarily to a more robust myofibroblast activation response, providing evidence that CF accumulation and myofibroblast activation may be mutually antagonistic. To investigate the contribution p53 to CF accumulation and fibrosis in mouse heart disease models, we deleted floxed p53 alleles specifically in adult CF using the tamoxifen-inducible Tcf21 MerCreMer mouse line (called p53-CKO). Surprisingly, while p53-CKO animals display exaggerated accumulation of Tcf21 + /PDGFRα + CF in response to left ventricle pressure overload, we observed a biphasic physiological response; initially, p53-CKO animals are resistant to systolic functional decline, only developing more severe fibrosis and functional decline than littermate controls at later time points. Time course studies using primary adult mouse CF revealed that p53 positively correlates with myofibroblast activation, while reduction in p53 levels correlates with accelerated cell cycle and the suppression of myofibroblast activation until the subsequent induction of p16/19 - Rb-mediated cell cycle arrest. Taken together, this study offers detailed insight into the transition of CF from a proliferative to an activated state that may accelerate the development of anti-fibrotic strategies.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.125.suppl_1.511
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1467838-X
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  • 10
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    Online Resource
    p53 Regulates the Extent of Fibroblast Proliferation and Fibrosis in Left Ventricle Pressure Overload
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Circulation Research Vol. 133, No. 3 ( 2023-07-21), p. 271-287
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 133, No. 3 ( 2023-07-21), p. 271-287
    Abstract: Cardiomyopathy is characterized by the pathological accumulation of resident cardiac fibroblasts that deposit ECM (extracellular matrix) and generate a fibrotic scar. However, the mechanisms that control the timing and extent of cardiac fibroblast proliferation and ECM production are not known, hampering the development of antifibrotic strategies to prevent heart failure. METHODS: We used the Tcf21 (transcription factor 21) MerCreMer mouse line for fibroblast-specific lineage tracing and p53 (tumor protein p53) gene deletion. We characterized cardiac physiology and used single-cell RNA-sequencing and in vitro studies to investigate the p53-dependent mechanisms regulating cardiac fibroblast cell cycle and fibrosis in left ventricular pressure overload induced by transaortic constriction. RESULTS: Cardiac fibroblast proliferation occurs primarily between days 7 and 14 following transaortic constriction in mice, correlating with alterations in p53-dependent gene expression. p53 deletion in fibroblasts led to a striking accumulation of Tcf21-lineage cardiac fibroblasts within the normal proliferative window and precipitated a robust fibrotic response to left ventricular pressure overload. However, excessive interstitial and perivascular fibrosis does not develop until after cardiac fibroblasts exit the cell cycle. Single-cell RNA sequencing revealed p53 null fibroblasts unexpectedly express lower levels of genes encoding important ECM proteins while they exhibit an inappropriately proliferative phenotype. in vitro studies establish a role for p53 in suppressing the proliferative fibroblast phenotype, which facilitates the expression and secretion of ECM proteins. Importantly, Cdkn2a (cyclin-dependent kinase inhibitor 2a) expression and the p16 Ink4a -retinoblastoma cell cycle control pathway is induced in p53 null cardiac fibroblasts, which may eventually contribute to cell cycle exit and fulminant scar formation. CONCLUSIONS: This study reveals a mechanism regulating cardiac fibroblast accumulation and ECM secretion, orchestrated in part by p53-dependent cell cycle control that governs the timing and extent of fibrosis in left ventricular pressure overload.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.121.320324
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1467838-X
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