Chapter 8 Molecular and cellular stress pathways in ischemic heart disease: Targets for regulated gene therapy

Keith A Webster

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Reperfusion damage to cardiac myocytes through the generation of excess ROIs is a central feature of ischemic heart disease. One of the earliest effects of reperfusion-generated ROIs is the activation of the c-Jun-N-terminal kinase JNK/SAPK pathway. The contribution of activated JNK to cell fate in this setting is currently not firmly established but recent work from the authors' laboratory indicates that the inhibition of JNK with a dominant negative JNK mutant promoted an increase in apoptosis of cardiac myocytes after hypoxia-reoxygenation. This clearly suggests that JNK activation is protective in this setting (Dougherty et al., 1999). Both JNK/SAPK activation and cell death by apoptosis can be blocked by pretreating heart cells with antioxidants. A second kinase pathway involving IP(3)K and Akt is anti-apoptotic and may also contribute to ischemia-mediated cell death. Activation of this pathway by exposure to insulin-like growth factor-1 (IGF-1) can protect cardiac myocytes from ischemia-reperfusion-mediated apoptosis. New gene therapy techniques designed to modulate these kinase pathway activities using novel heart-specific and hypoxia-regulated vectors may eventually replace current pharmacological and surgical methods to treat CAD and myocardial ischemia.

Original languageEnglish
Pages (from-to)99-112
Number of pages14
JournalCell and Molecular Response to Stress
Issue numberC
StatePublished - Dec 1 2000

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology


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