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  • Medizin  (4)
  • 1
    Online-Ressource
    Online-Ressource
    Role of Ion Channels and Exchangers in Mechanical Stretch–Induced Cardiomyocyte Hypertrophy
    Ovid Technologies (Wolters Kluwer Health) ; 1998
    In:  Circulation Research Vol. 82, No. 4 ( 1998-03-09), p. 430-437
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 82, No. 4 ( 1998-03-09), p. 430-437
    Kurzfassung: Abstract —We have previously reported that stretching of cardiomyocytes activates the phosphorylation cascade of protein kinases, including Raf-1 kinase and mitogen-activated protein (MAP) kinases, followed by an increase in protein synthesis partly through enhanced secretion of angiotensin II and endothelin-1. Membrane proteins, such as ion channels and exchangers, have been postulated to first receive extracellular stimuli and evoke intracellular signals. The present study was performed to determine whether mechanosensitive ion channels and exchangers are involved in stretch-induced hypertrophic responses. Neonatal rat cardiomyocytes cultured on expandable silicone dishes were stretched after pretreatment with a specific inhibitor of stretch-sensitive cation channels (gadolinium and streptomycin), of ATP-sensitive K + channels (glibenclamide), of hyperpolarization-activated inward channels (CsCl), or of the Na + -H + exchanger (HOE 694). Pretreatment with gadolinium, streptomycin, glibenclamide, and CsCl did not show any inhibitory effects on MAP kinase activation by mechanical stretch. HOE 694, however, markedly attenuated stretch-induced activation of Raf-1 kinase and MAP kinases by ≈50% and 60%, respectively, and attenuated stretch-induced increase in phenylalanine incorporation into proteins. In contrast, HOE 694 did not inhibit angiotensin II–and endothelin-1–induced Raf-1 kinase and MAP kinase activation. These results suggest that among many mechanosensitive ion channels and exchangers, the Na + -H + exchanger plays a critical role in mechanical stress–induced cardiomyocyte hypertrophy.
    Materialart: Online-Ressource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.82.4.430
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 1998
    ZDB Id: 1467838-X
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
  • 2
    Online-Ressource
    Online-Ressource
    Molecular Cloning and Characterization of Human Cardiac Homeobox Gene CSX1
    Ovid Technologies (Wolters Kluwer Health) ; 1996
    In:  Circulation Research Vol. 79, No. 5 ( 1996-11), p. 920-929
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 79, No. 5 ( 1996-11), p. 920-929
    Kurzfassung: Accumulating evidence has suggested that homeodomain-containing proteins play critical roles in regulating the tissue-specific gene expression essential for tissue differentiation and in determining the temporal and spatial patterns of development. In order to elucidate the mechanisms of human heart development, we have isolated a human homologue of the murine cardiac homeobox gene Csx (also called Nkx-2.5) and denoted it as CSX1. The amino acid sequence of the CSX1 homeodomain is 100% and 67% identical to that of murine Csx/Nkx-2.5 and Drosophila tinman, respectively. CSX1 has at least three isoforms generated by an alternative splicing mechanism. One of these isoforms ( CSX1a ) encodes a protein of ≈35 kD that possesses the homeodomain, whereas the other two ( CSX1b and CSX1c ) encode a truncated protein of ≈12 kD that is identical to the CSX1a protein at the amino-terminal 112 amino acids but lacks the homeodomain. Northern blot analysis showed that CSX1 transcripts are abundantly expressed in both fetal and adult hearts, but no signal was detected in other human tissues examined. Amplification of each isoform by reverse transcriptase–polymerase chain reaction revealed that all of the three isoforms are expressed in fetal and adult hearts and that the homeobox-containing isoform CSX1a is most abundant. The homeodomain-containing protein encoded by CSX1a binds to Csx/Nkx-2.5 binding sequences and transactivates the sequence-containing luciferase reporter gene. Unexpectedly, the homeodomain-lacking protein encoded by CSX1b also transactivates the reporter gene, although CSX1b does not bind to the Csx / Nkx-2.5 binding sequences. The highly conserved homeodomain sequence in evolution and the restricted expression in the heart suggest that CSX1 plays an important role in the development and differentiation of the human heart and that there may be two different mechanisms in transcriptional regulation by the CSX1 protein, homeodomain-dependent and -independent mechanisms.
    Materialart: Online-Ressource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.79.5.920
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 1996
    ZDB Id: 1467838-X
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
  • 3
    Online-Ressource
    Online-Ressource
    Rho Family Small G Proteins Play Critical Roles in Mechanical Stress–Induced Hypertrophic Responses in Cardiac Myocytes
    Ovid Technologies (Wolters Kluwer Health) ; 1999
    In:  Circulation Research Vol. 84, No. 4 ( 1999-03-05), p. 458-466
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 84, No. 4 ( 1999-03-05), p. 458-466
    Kurzfassung: Abstract —Mechanical stress induces a variety of hypertrophic responses, such as activation of protein kinases, reprogramming of gene expression, and an increase in protein synthesis. In the present study, to elucidate how mechanical stress induces such events, we examined the role of Rho family small GTP-binding proteins (G proteins) in mechanical stress–induced cardiac hypertrophy. Treatment of neonatal rat cardiomyocytes with the C3 exoenzyme, which abrogates Rho functions, suppressed stretch-induced activation of extracellular signal–regulated protein kinases (ERKs). Overexpression of the Rho GDP dissociation inhibitor (Rho-GDI), dominant-negative mutants of RhoA (DNRhoA), or DNRac1 significantly inhibited stretch-induced activation of transfected ERK2. Overexpression of constitutively active mutants of RhoA slightly activated ERK2 in cardiac myocytes. Overexpression of C -terminal Src kinase, which inhibits functions of the Src family of tyrosine kinases, or overexpression of DNRas had no effect on stretch-induced activation of transfected ERK2. The promoter activity of skeletal α-actin and c- fos genes was increased by stretch, and these increases were completely inhibited by either cotransfection of Rho-GDI or pretreatment with C3 exoenzyme. Mechanical stretch increased phenylalanine incorporation into cardiac myocytes by ≈1.5-fold compared with control, and this increase was also significantly suppressed by pretreatment with C3 exoenzyme. Overexpression of Rho-GDI or DNRhoA did not affect angiotensin II–induced activation of ERK. ERKs were activated by culture media conditioned by stretch of cardiomyocytes without any treatment, but not of cardiomyocytes with pretreatment by C3 exoenzyme. These results suggest that the Rho family of small G proteins plays critical roles in mechanical stress–induced hypertrophic responses.
    Materialart: Online-Ressource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.84.4.458
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 1999
    ZDB Id: 1467838-X
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
  • 4
    Online-Ressource
    Online-Ressource
    Cell Type–Specific Angiotensin II–Evoked Signal Transduction Pathways : Critical Roles of G βγ Subunit, Src Family, and Ras in Cardiac Fibroblasts
    Ovid Technologies (Wolters Kluwer Health) ; 1998
    In:  Circulation Research Vol. 82, No. 3 ( 1998-02-23), p. 337-345
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 82, No. 3 ( 1998-02-23), p. 337-345
    Kurzfassung: Abstract —Angiotensin II (Ang II) induces hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. To determine the molecular mechanism by which Ang II displayed different effects on cardiac myocytes and fibroblasts, we examined signal transduction pathways leading to activation of extracellular signal–regulated kinases (ERKs). Ang II–induced ERK activation was abolished by pretreatment with pertussis toxin and by overexpression of the G βγ subunit–binding domain of the β-adrenergic receptor kinase 1 in cardiac fibroblasts but not in cardiac myocytes. Inhibition of protein kinase C strongly inhibited activation of ERKs by Ang II in cardiac myocytes, whereas inhibitors of tyrosine kinases but not of protein kinase C abolished Ang II–induced ERK activation in cardiac fibroblasts. Overexpression of C-terminal Src kinase (Csk), which inactivates Src family tyrosine kinases, suppressed the activation of transfected ERK in cardiac fibroblasts. Ang II rapidly induced phosphorylation of Shc and association of Shc with Grb2. Cotransfection of the dominant-negative mutant of Ras or Raf-1 kinase abolished Ang II–induced ERK activation in cardiac fibroblasts. Overexpression of Csk or the dominant-negative mutant of Ras had no effects on Ang II–induced ERK activation in cardiac myocytes. These findings suggest that Ang II–evoked signal transduction pathways differ among cell types. In cardiac fibroblasts, Ang II activates ERKs through a pathway including the G βγ subunit of G i protein, tyrosine kinases including Src family tyrosine kinases, Shc, Grb2, Ras, and Raf-1 kinase, whereas G q and protein kinase C are important in cardiac myocytes.
    Materialart: Online-Ressource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/01.RES.82.3.337
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 1998
    ZDB Id: 1467838-X
    Standort Signatur Einschränkungen Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Online-Ressource
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