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  • 1
    Online Resource
    Online Resource
    ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation: Heart Failure Vol. 14, No. 7 ( 2021-07)
    Details
    In: Circulation: Heart Failure, Ovid Technologies (Wolters Kluwer Health), Vol. 14, No. 7 ( 2021-07)
    Abstract: Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene Erbb4 is a common driving factor of PPCM. Methods: miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific Erbb4 mice ( Erbb4 F/+ αMHC-Cre + , n=9) with their age-matched nonpregnant CTRLs (n=9–10). Results: Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (−29% to −50%; P 〈 0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of Erbb4 during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL; P 〈 0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice, P 〈 0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (−33±17%, P =0.07; −27±20%, P 〈 0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL, P 〈 0.05) but without signs of myocardial apoptosis and inflammation. Conclusions: ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00998556.
    Type of Medium: Online Resource
    ISSN: 1941-3289 , 1941-3297
    URL: Article
    DOI: 10.1161/CIRCHEARTFAILURE.120.006898
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2428100-1
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  • 2
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    Online Resource
    Interleukin-1 Assembles a Proangiogenic Signaling Module Consisting of Caveolin-1, Tumor Necrosis Factor Receptor–Associated Factor 6, p38–Mitogen-Activated Protein Kinase (MAPK), and MAPK-Activated Protein Kinase 2 in Endothelial Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2012
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 32, No. 5 ( 2012-05), p. 1280-1288
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 5 ( 2012-05), p. 1280-1288
    Abstract: Interleukin-1β (IL-1β) is a major cytokine linking inflammation and angiogenesis in pathological vascular processes, such as atherosclerosis and tumor neoangiogenesis. However, signaling pathways mediating IL-1β-induced proangiogenic processes in endothelial cells (ECs) have barely been elucidated yet. Therefore, the present study investigated IL-1β-induced proangiogenic signaling in ECs. Methods and Results— IL-1β potently induced tube formation and migration of ECs. This was associated with and dependent on activation of p38–mitogen-activated protein kinase (MAPK) and MAPK-activated protein kinase 2 (MK2) as determined by pharmacological inhibition and gene silencing. Furthermore, silencing of the adaptor protein tumor necrosis factor receptor–associated factor 6 (TRAF6) (lentiviral short hairpin RNA) inhibited these IL-1β-induced processes. Moreover, IL-1β promoted translocation of TRAF6 to insoluble cellular fractions (containing membrane rafts/caveolae) and interaction of TRAF6 with caveolin-1. Accordingly, cellular cholesterol depletion (cyclodextrin) and silencing of caveolin-1 (small interfering RNA) inhibited IL-1β-induced activation of p38-MAPK and MK2, as well as IL-1β-induced tube formation and migration. Finally, silencing of TRAF6 and MK2 deficiency inhibited IL-1β-induced microvessel outgrowth in murine aortic rings ex vivo, and deficiency of MK2 or caveolin-1 significantly reduced IL-1β-induced angiogenesis in mice in vivo (Matrigel plug assay). Conclusion— IL-1β assembles a proangiogenic signaling module consisting of caveolin-1, TRAF6, p38-MAPK, and MK2 in ECs, representing a potential target to intervene into angiogenesis-dependent processes and diseases.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.111.243477
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2012
    detail.hit.zdb_id: 1494427-3
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  • 3
    Online Resource
    Online Resource
    Continuous Glycoprotein-130–Mediated Signal Transducer and Activator of Transcription-3 Activation Promotes Inflammation, Left Ventricular Rupture, and Adverse Outcome in Subacute Myocardial Infarction
    Ovid Technologies (Wolters Kluwer Health) ; 2010
    In:  Circulation Vol. 122, No. 2 ( 2010-07-13), p. 145-155
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 122, No. 2 ( 2010-07-13), p. 145-155
    Abstract: Background— In patients with myocardial infarction, high serum levels of interleukin-6 cytokines predict a poor outcome. The common receptor of interleukin-6 cytokines, glycoprotein-130 (gp130), signals via janus kinase/signal transducer and activator of transcription (STAT), cytoplasmic protein tyrosine phosphatase/extracellular signal-regulated kinase, and phosphoinositide-3-kinase/Akt pathways, and the regulation of these pathways depends at least in part on the gp130 tyrosine-757 residue. By analyzing cardiomyocyte-specific gp130 Y757F mutant mice, we investigated the effect of disturbed gp130 signaling after myocardial infarction. Methods and Results— The cardiomyocyte-restricted α-myosin heavy chain-Cre-recombinase-loxP system was used to generate mice with gp130 Y757F mutant cardiomyocytes ( αMHC-Cre tg/− ;gp130 fl/Y757F [Y 757 F]); all other cells carried at least 1 functional gp130 gene, ensuring normal gp130 signaling. Y 757 F mice displayed normal cardiac function and morphology at 3 months of age comparable to their nonmutant littermates. In response to myocardial infarction, Y 757 F mice displayed higher mortality associated with increased left ventricular rupture rate, sustained cardiac inflammation, and heart failure. These adverse effects were associated with prolonged and enhanced STAT3 activation and increased expression of interleukin-6 and of the complement-activating mannose-binding lectin C. Pharmacological inhibition of the complement system by cobra venom factor attenuated inflammation, prevented left ventricular rupture, and improved cardiac function in Y 757 F mice. Stronger effects were observed with a genetic reduction of STAT3 (STAT3 flox/+ ) restricted to cardiomyocytes in Y 757 F mice, which prevented extensive upregulation of interleukin-6, complement activation, and sustained inflammation and lowered left ventricular rupture rate, heart failure, and mortality in subacute myocardial infarction. Conclusion— Impaired downregulation of gp130-mediated STAT3 activation in subacute infarction promotes cardiac inflammation, adverse remodeling, and heart failure, suggesting a potential causative role of high interleukin-6 serum levels after myocardial infarction.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.109.933127
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2010
    detail.hit.zdb_id: 1466401-X
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