Overexpression of cardiac I-κBα prevents endotoxin-induced myocardial dysfunction

Sandra B. Haudek, Erika Spencer, Debora D. Bryant, D. Jean White, David Maass, Jureta W. Horton, Zhijian J. Chen, Brett P. Giroir

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

Nuclear factor-κ B (NF-κB) is an inducible transcription factor that regulates expression of many genes, such as tumor necrosis factor-α (TNF-α), which may contribute to myocardial dysfunction. We investigated whether cardiac NF-κB activation is involved in the development of myocardial dysfunction after lipopolysaccharide (LPS) challenge. Mice were intraperitoneally injected with LPS, and the hearts were harvested and assayed for NF-κB translocation. After LPS challenge, NF-κB activation was detected within 30 min and remained for 8 h. In transgenic mice constitutively overexpressing a nondegradable form of I-κBα (I-κBαΔN) in cardiomyocytes, myocardial NF-κB translocation was prevented after LPS challenge. Myocytes isolated from these transgenics secreted significantly less TNF-α than did wild-type cardiomyocytes after LPS stimulation. When whole hearts were excised, perfused in a Langendorff preparation, and challenged with endotoxin, I-κBαΔN transgenic hearts displayed normal cardiac function, whereas profound contractile dysfunction was observed in wild-type hearts. These data indicate that myocardial NF-κB translocates within minutes after LPS administration. Inhibition of myocyte NF-κB activation by overexpression of myocyte I-κBα is sufficient to block cardiac TNF-α production and prevent cardiac dysfunction after LPS challenge.

Original languageEnglish (US)
Pages (from-to)H962-H968
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume280
Issue number3 49-3
DOIs
StatePublished - 2001

Keywords

  • Signaling pathways
  • Transcription factor
  • Transgenic mice
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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