GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
Material
Publisher
Person/Organisation
Language
Years
FID
Subjects(RVK)
  • 1
    Online Resource
    Online Resource
    Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 145, No. 22 ( 2022-05-31), p. 1663-1683
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 145, No. 22 ( 2022-05-31), p. 1663-1683
    Abstract: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. Methods: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high–throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell–derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis. Results: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer–promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell–derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell–derived cardiomyocytes induced a distinct gain of enhancer–promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell–derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca 2+ handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. Conclusions: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer–promoter connectome to drive DCM pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.121.055781
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 20232: Haploinsufficiency of MYBPC3 in the Development of Hypertrophic Cardiomyopathy
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Circulation Vol. 130, No. suppl_2 ( 2014-11-25)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)
    Abstract: Introduction: Mutations in MYBPC3, encoding cardiac myosin binding protein-C (cMyBP-C), account for ~40% of hypertrophic cardiomyopathy (HCM) cases. MYBPC3 mutations are usually encode truncated proteins and are not found in tissue and are typically heterozygous (Het) in humans. Reduced protein levels occur in human HCM patients with these mutations, suggesting haploinsufficiency. However, it is unknown if cMyBP-C reduction causes or results from hypertrophy. Hypothesis: To test whether haploinsufficiency occurs following cardiac stress and if heterozygous MYBPC3 mice had worsened disease progression. Methods & Results: Transverse aortic constriction (TAC) was performed on 3 month old wild type (WT) and Het MYBPC3 truncation mutant mice which were allowed to hypertrophy for 4 or 12 weeks. Het TAC mice showed increased hypertrophy 12 weeks post-TAC compared to WT TAC controls. Het TAC hearts showed reduced ejection fraction compared to WT TAC at 4 and 12 weeks. MYBPC3 transcript levels were significantly reduced in sham and TAC Het hearts. cMyBP-C levels decreased in Het sham and TAC at 4 weeks but returned to baseline levels at 12 weeks. Het TAC myocytes showed higher Ca2+ sensitivity at 4 weeks, and impaired maximal force development. Het sham and TAC skinned cardiomyocytes showed reduced length dependent increases in Ca2+ sensitivity and maximal force development. RNA-Seq shows no alterations in proteasome of RNA-degradation pathways which have been suggested to play a role in the pathology of these mutations. Overexpression of WT cMyBP-C in the presence of truncated MYBPC3 rescued the decline in force observed in Het myocytes in the absence of stress. Conclusions: Heterozygous MYBPC3 truncation mutant carriers develop more profound hypertrophy and dysfunction following stress. Also, increased MYBPC3 expression reverses myocyte deficits in force generation in the presence of truncated alleles.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.130.suppl_2.20232
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1466401-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Epigenetic modification: a regulatory mechanism in essential hypertension
    Springer Science and Business Media LLC ; 2019
    In:  Hypertension Research Vol. 42, No. 8 ( 2019-08), p. 1099-1113
    Details
    In: Hypertension Research, Springer Science and Business Media LLC, Vol. 42, No. 8 ( 2019-08), p. 1099-1113
    Type of Medium: Online Resource
    ISSN: 0916-9636 , 1348-4214
    URL: Article
    DOI: 10.1038/s41440-019-0248-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 2110941-2
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Abstract P251: Mechanical Stretch Induces Phosphorylation of Cardiac Myosin Binding Protein-C
    Ovid Technologies (Wolters Kluwer Health) ; 2011
    In:  Circulation Research Vol. 109, No. suppl_1 ( 2011-12-09)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 109, No. suppl_1 ( 2011-12-09)
    Abstract: Normal hearts increase contractile force in response to mechanical stretch caused by increasing volume. Although this phenomenon has been extensively studied from myofilaments’ spacing perspective, possible coupling of mechanical-sensing signaling to modulation of myofilament function remains unknown. Cardiac myosin binding protein-C (MyBPC3) is a component of heart muscle thick filament. Phosphorylation of MyBPC3 releases its inhibition on cross-bridge cycling to increase cardiac contractility. Thus, we postulate that mechanical stretch of the myocardium causes phosphorylation of MyBPC3 to increase contractility. We tested this hypothesis by performing static stretch of 20% from baseline on cultured neonatal rat cardiac myocytes (NRCM) at durations of 2, 5, 15, 30, and 60 minutes. NRCM culture provides the advantage of cells living in an environment free of adrenergic stimulation to avoid catecholamine stimulation mediated phosphorylation of MyBPC3. Site-specific phospho-serine antibodies were used to detect phosphorylation of rat equivalent of S282 and S302 of mouse MyBPC3. We used MyBPC3 antibody made from a different species than site-specific phospho-serine antibodies to account for loading. S282P transiently peaked after 5 minutes of stretch, whereas S302P continued to increase with time through 60 minutes (see figure ). Consequently, our data show that mechanical stretch alone can cause phosphorylation of MyBPC3 as a mechanism that couples different signaling pathways to myofilament function.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.109.suppl_1.AP251
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2011
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Transgenic Rabbit Model for Human Troponin I–Based Hypertrophic Cardiomyopathy
    Ovid Technologies (Wolters Kluwer Health) ; 2005
    In:  Circulation Vol. 111, No. 18 ( 2005-05-10), p. 2330-2338
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 111, No. 18 ( 2005-05-10), p. 2330-2338
    Abstract: Background— Transgenic and gene-targeted models have focused on the mouse. Fundamental differences between the mouse and human exist in Ca 2+ handling during contraction/relaxation and in alterations in Ca 2+ flux during heart failure, with the rabbit more accurately reflecting the human system. Methods and Results— Cardiac troponin I (cTnI) mutations can cause familial hypertrophic cardiomyopathy. An inhibitory domain mutation, arginine146→glycine (cTnI 146Gly ), was modeled with the use of transgenic expression in the rabbit ventricle. cTnI 146Gly levels 〉 40% of total cTnI were perinatally lethal, whereas replacement levels of 15% to 25% were well tolerated. cTnI 146Gly expression led to a leftward shift in the force-pCa 2+ curves with cardiomyocyte disarray, fibrosis, and altered connexin43 organization. In isolated cTnI 146Gly myocytes, twitch relaxation amplitudes were smaller than in normal cells, but [Ca] i transients and sarcoplasmic reticulum Ca 2+ load were not different. Detrended fluctuation analysis of the QT max intervals was used to evaluate the cardiac repolarization phase and showed a significantly higher scaling exponent in the transgenic animals. Conclusions— Expression of modest amounts of cTnI 146Gly led to subtle defects without severely affecting cardiac function. Aberrant connexin organization, subtle morphological deficits, and an altered fractal pattern of the repolarization phase of transgenic rabbits, in the absence of entropy or other ECG abnormalities, may indicate an early developing pathology before the onset of more obvious repolarization abnormalities or major alterations in cardiac mechanics.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/01.CIR.0000164234.24957.75
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2005
    detail.hit.zdb_id: 1466401-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Cardiac Myosin-Binding Protein-C Phosphorylation and Cardiac Function
    Ovid Technologies (Wolters Kluwer Health) ; 2005
    In:  Circulation Research Vol. 97, No. 11 ( 2005-11-25), p. 1156-1163
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 97, No. 11 ( 2005-11-25), p. 1156-1163
    Abstract: The role of cardiac myosin binding protein-C (cMyBP-C) phosphorylation in cardiac physiology or pathophysiology is unclear. To investigate the status of cMyBP-C phosphorylation in vivo, we determined its phosphorylation state in stressed and unstressed mouse hearts. cMyBP-C phosphorylation is significantly decreased during the development of heart failure or pathologic hypertrophy. We then generated transgenic (TG) mice in which the phosphorylation sites of cMyBP-C were changed to nonphosphorylatable alanines (MyBP-C AllP− ). A TG line showing & 40% replacement with MyBP-C AllP− showed no changes in morbidity or mortality but displayed depressed cardiac contractility, altered sarcomeric structure and upregulation of transcripts associated with a hypertrophic response. To explore the effect of complete replacement of endogenous cMyBP-C with MyBP-C AllP− , the mice were bred into the MyBP-C (t/t) background, in which less than 10% of normal levels of a truncated MyBP-C are present. Although MyBP-C AllP− was incorporated into the sarcomere and expressed at normal levels, the mutant protein could not rescue the MyBP-C (t/t) phenotype. The mice developed significant cardiac hypertrophy with myofibrillar disarray and fibrosis, similar to what was observed in the MyBP-C (t/t) animals. In contrast, when the MyBP-C (t/t) mice were bred to a TG line expressing normal MyBP-C (MyBP-C WT ), the MyBP-C (t/t) phenotype was rescued. These data suggest that cMyBP-C phosphorylation is essential for normal cardiac function.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.0000190605.79013.4d
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2005
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Abstract P1043: Myocardial Infarction Induces Translocation Of Gut Bacteria To The Heart
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Research Vol. 131, No. Suppl_1 ( 2022-08-05)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. Suppl_1 ( 2022-08-05)
    Abstract: Introduction: Myocardial hypoxia & intestinal hyperpermeability (IH) are two important events commonly observed in the aftermath of a myocardial infarction (MI) event. Recent studies have shown that gut bacteria and their metabolites are able to leak into the systemic circulation due to post-MI IH. Hypothesis: We hypothesized that facultative anaerobic gut bacteria such as E. coli will be able to translocate and colonize the hypoxic heart post-MI. Methods: C57 mice were given an oral administration of 10e9 cfu of luciferase/GFP expressing E. coli Nissle (EcN). Permanent occlusion of LAD arteries was performed to induce MI. Mouse hearts were checked for presence of EcN using PCR at different timepoints (n=32), IHC (n=4), and siderophore-based PET imaging (n=2). Immunoblotting of heart tissue lysate was used to check for presence of GFP. Results: PCR amplification of DNA extracted from MI hearts of mice given oral EcN revealed cardiac presence of translocated EcN. IHC analysis further confirmed presence of EcN in the heart. Siderophore-based PET imaging & radionuclide-based biodistribution studies revealed significantly higher uptake in the MI heart vs. Sham corroborating EcN presence. Immunoblotting revealed presence of GFP in cardiac tissue of MI mice suggesting that bacterial products and proteins could potentially translocate through the gut-heart axis. Conclusion: MI induced IH & myocardial hypoxia contribute to the translocation of gut bacteria and colonization of the ischemic heart.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.131.suppl_1.P1043
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Abstract 915: Dysregulation of the Myosin and Myosin Binding Protein-C interaction in Hypertrophic Cardiomyopathy
    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: Rationale: Affecting 1 in 300 individuals, hypertrophic cardiomyopathy (HCM) is a genetic heart disease characterized by left ventricular hypertrophy, myocardial disarray, and sudden cardiac death. Often, HCM is associated with myocardial hypercontractility. The subfragment-2 (S2) of beta-myosin heavy chain contains a cluster of missense and deletion mutations associated with severe HCM. Interestingly, myosin S2 interacts with the C0-C2 region of cardiac myosin binding protein C (cMyBP-C) in a phosphorylation-dependent manner to regulate sarcomere contractility. However, the nature of myosin S2 and cMyBP-C interactions and the mechanism(s) by which mutations in myosin S2 cause HCM remain to be elucidated. Objective: To determine whether mutations in myosin S2 weaken its interaction with cMyBP-C, resulting in enhanced myofilament contractility. Methods and Results: Myosin S2 proteins (126 amino acids) containing three clinically relevant mutations (R870H, E924K, E930del, or wild type), and recombinant C0-C2 region of cMyBP-C were produced and purified by metal affinity chromatography. Solid-phase binding assays and isothermal calorimetry experiments revealed a significantly dampened binding to C0-C2 for these three mutants in myosin S2 (30% lower than wild type, p 〈 0.002), suggesting that mutations in S2 regions reduce their bindings to cMyBP-C. Conversely, upon protein kinase A phosphorylation of C0C2, these S2 mutants displayed an increased affinity to cMyBP-C, an effect opposite that of wild-type S2. Structural analyses of these mutations within myosin S2 are predicted to reduce the alpha-helical content, thereby reducing stability of the critical coiled-coil structure. Conclusions: Mutations in myosin S2 result in reduced binding to cMyBP-C. Functionally, this would result in a greater attachment of cross-bridges, and thus enhance myofilament contractility. Strikingly, these mutations increase their affinity to cMyBP-C upon phosphorylation, demonstrating fundamental changes to the regulation of contractile function.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.125.suppl_1.915
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle
    Rockefeller University Press ; 2023
    In:  Journal of General Physiology Vol. 155, No. 4 ( 2023-04-03)
    Details
    In: Journal of General Physiology, Rockefeller University Press, Vol. 155, No. 4 ( 2023-04-03)
    Abstract: The myosin super-relaxed (SRX) state is central to striated muscle metabolic and functional regulation. In skeletal muscle, SRX myosin are predominantly colocalized with myosin-binding protein C (MyBP-C) in the sarcomere C-zone. To define how cardiac MyBP-C (cMyBP-C) and its specific domains contribute to stabilizing the SRX state in cardiac muscle, we took advantage of transgenic cMyBP-C null mice and those expressing cMyBP-C with a 271-residue N-terminal truncation. Utilizing super-resolution microscopy, we determined the lifetime and subsarcomeric location of individual fluorescent-ATP turnover events within isolated cardiac myofibrils. The proportion of SRX myosin demonstrated a gradient along the half-thick filament, highest in the P- and C-zones (72 ± 9% and 71 ± 6%, respectively) and lower in the D-zone (45 ± 10%), which lies farther from the sarcomere center and lacks cMyBP-C, suggesting a possible role for cMyBP-C in stabilizing the SRX. However, myofibrils from cMyBP-C null mice demonstrated an ∼40% SRX reduction, not only within the now cMyBP-C-free C-zone (49 ± 9% SRX), but also within the D-zone (22 ± 5% SRX). These data suggest that the influence of cMyBP-C on the SRX state is not limited to the C-zone but extends along the thick filament. Interestingly, myofibrils with N-terminal truncated cMyBP-C had an SRX content and spatial gradient similar to the cMyBP-C null, indicating that the N terminus of cMyBP-C is necessary for cMyBP-C’s role in enhancing the SRX gradient along the entire thick filament. Given that SRX myosin exist as a gradient along the thick filament that is highest in the C-zone, even in the absence of cMyBP-C or its N-terminus, an inherent bias must exist in the structure of the thick filament to stabilize the SRX state.
    Type of Medium: Online Resource
    ISSN: 0022-1295 , 1540-7748
    URL: Article
    DOI: 10.1085/jgp.202213276
    Language: English
    Publisher: Rockefeller University Press
    Publication Date: 2023
    detail.hit.zdb_id: 1477246-2
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling
    Springer Science and Business Media LLC ; 2023
    In:  Communications Biology Vol. 6, No. 1 ( 2023-11-25)
    Details
    In: Communications Biology, Springer Science and Business Media LLC, Vol. 6, No. 1 ( 2023-11-25)
    Abstract: The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts expressing increased levels of CD4, a helper T-cell marker, in addition to myofibroblast markers distributed in human fibrotic RV tissue, interstitial and perivascular lesions in SUGEN/Hypoxia (SuHx) rats, and fibroblasts labeled with pdgfrα CreERt2/+ in R26R-tdTomato mice. Recombinant IL-1β increases IL-1R, CCR2 receptor expression, modifies the secretome, and differentiates cardiac fibroblasts to form CD68-positive cell clusters. IL-1β also activates stemness markers, such as NANOG and SOX2, and genes involved in dedifferentiation, lymphoid cell function and metabolic reprogramming. IL-1β induction of lineage traced primary mouse cardiac fibroblasts causes these cells to lose their fibroblast identity and acquire an immune phenotype. Our results identify IL-1β induced immune-competency in human cardiac fibroblasts and suggest that fibroblast secretome modulation may constitute a therapeutic approach to PAH and other diseases typified by inflammation and fibrotic remodeling.
    Type of Medium: Online Resource
    ISSN: 2399-3642
    URL: Article
    DOI: 10.1038/s42003-023-05463-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2919698-X
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...