Suppression of the JNK pathway by induction of a metabolic stress response prevents vascular injury and dysfunction.

Abstract

BACKGROUND:

Oxidative injury and dysfunction of the vascular endothelium are early and causal features of many vascular diseases. Single antioxidant strategies to prevent vascular injury have met with mixed results.

METHODS AND RESULTS:

Here, we report that induction of a metabolic stress response with adenosine monophosphate kinase (AMPK) prevents oxidative endothelial cell injury. This response is characterized by stabilization of the mitochondrion and increased mitochondrial biogenesis, resulting in attenuation of oxidative c-Jun N-terminal kinase (JNK) activation. We report that peroxisome proliferator coactivator 1alpha is a key downstream target of AMPK that is both necessary and sufficient for the metabolic stress response and JNK attenuation. Moreover, induction of the metabolic stress response in vivo attenuates reactive oxygen species-mediated JNK activation and endothelial dysfunction in response to angiotensin II in wild-type mice but not in animals lacking either the endothelial isoform of AMPK or peroxisome proliferator coactivator 1alpha.

CONCLUSIONS:

These data highlight AMPK and peroxisome proliferator coactivator 1alpha as potential therapeutic targets for the amelioration of endothelial dysfunction and, as a consequence, vascular disease.

• Authors: Eberhard Schulz, Jörn Dopheide, Swenja Schuhmacher, Shane R Thomas, Kai Chen, Andreas Daiber, Philip Wenzel, Thomas Münzel, John F Keaney Jr
• Journal: Circulation (Circulation) Vol. 118 Issue 13 Pg. 1347-57 (Sep 23 2008) ISSN: 1524-4539 [Electronic] United States
• PMID: 18809807 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Heat-Shock Proteins
• Oxidants
• PPARGC1A protein, human
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• RNA, Small Interfering
• Ribonucleotides
• Transcription Factors
• Aminoimidazole Carboxamide
• Hydrogen Peroxide
• JNK Mitogen-Activated Protein Kinases
• Adenylate Kinase
• AICA ribonucleotide

Topics

• Adaptation, Physiological (physiology)
• Adenylate Kinase (genetics, metabolism)
• Aminoimidazole Carboxamide (analogs & derivatives)
• Animals
• COS Cells
• Cell Death (physiology)
• Chlorocebus aethiops
• Endothelial Cells (cytology, drug effects, enzymology)
• Heat-Shock Proteins (metabolism)
• Humans
• Hydrogen Peroxide (pharmacology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Male
• Membrane Potential, Mitochondrial (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Mutagenesis
• Oxidants (pharmacology)
• Oxidative Stress (drug effects, physiology)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• RNA, Small Interfering
• Ribonucleotides
• Transcription Factors (metabolism)
• Umbilical Veins (cytology)
• Vascular Diseases (metabolism, pathology, prevention & control)