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Ischemic preconditioning exaggerates cardiac damage in PKC-delta null mice
Manuel Mayr1, Bernhard Metzler, Yuen-Li Chung
1Department of Cardiac and Vascular Sciences, St George's Hospital Medical School, London SW17 0RE, UK.
Summary
Ischemic preconditioning normally protects the heart, but knockout mice lacking protein kinase C-delta (PKC-delta) showed exaggerated injury. This suggests PKC-delta is crucial for preconditioning
Area of Science:
- Cardiovascular Physiology
- Mitochondrial Biology
- Enzyme Function
Background:
- Ischemic preconditioning (IP) protects the heart from ischemia-reperfusion (I/R) injury.
- Protein kinase C (PKC) plays a role in IP, but the specific function of the PKC-delta isoform remains controversial.
- Previous studies identified metabolic changes in PKC-delta knockout (PKC-delta(-/-)) mice.
Purpose of the Study:
- To investigate the role of PKC-delta in early ischemic preconditioning.
- To determine if the absence of PKC-delta affects cardiac protection during I/R injury.
- To explore the impact of PKC-delta deficiency on reactive oxygen species generation and metabolic adaptations following preconditioning.
Main Methods:
- Mice lacking PKC-delta (PKC-delta(-/-)) and wild-type (PKC-delta(+/+)) littermates underwent a preconditioning protocol (3 cycles of 5-min occlusion/5-min reperfusion).
- Hearts were subjected to a prolonged 30-min occlusion and 2-h reperfusion.
- Methods included assessment of reactive oxygen species (ROS) production, proteomic analysis of mitochondrial enzymes, and high-resolution NMR spectroscopy of cardiac metabolites.
Main Results:
- Contrary to expectations, preconditioning exacerbated I/R injury in PKC-delta(-/-) mice.
- Ischemic preconditioning increased superoxide anion production in wild-type hearts but not in PKC-delta(-/-) hearts.
- Proteomic analysis revealed fragmentation of mitochondrial enzymes in preconditioned wild-type hearts, which was absent in PKC-delta(-/-) hearts.
- Metabolic analysis showed impaired preconditioning-induced increases in phosphocholine, alanine, carnitine, and glycine in PKC-delta(-/-) hearts, with higher lactate levels.
Conclusions:
- Reactive oxygen species generated during ischemic preconditioning may oxidize and alter key mitochondrial enzymes involved in energy metabolism.
- The PKC-delta isoform is essential for the metabolic adaptations that mediate cardiac protection during ischemic preconditioning.
- Absence of PKC-delta impairs the beneficial metabolic response to preconditioning, leading to increased vulnerability to ischemia-reperfusion injury.