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Protein kinase C-dependent mitochondrial translocation of proapoptotic protein Bax on activation of inducible nitric-oxide synthase in rostral ventrolateral medulla mediates cardiovascular depression during experimental endotoxemia.
- Source :
-
Molecular pharmacology [Mol Pharmacol] 2007 Apr; Vol. 71 (4), pp. 1129-39. Date of Electronic Publication: 2007 Jan 16. - Publication Year :
- 2007
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Abstract
- Sympathetic premotor neurons for the maintenance of vasomotor tone are located in rostral ventrolateral medulla (RVLM). We demonstrated previously that overproduction of nitric oxide (NO) by inducible NO synthase (iNOS) in RVLM, leading to caspase 3-dependent apoptotic cell death, plays a pivotal role in cardiovascular depression during endotoxemia induced by intravenous administration of Escherichia coli lipopolysaccharide. The interposing intracellular events remain unknown. We evaluated the hypothesis that these events encompass protein kinase C (PKC) activation, which triggers activation and translocation of Bax that opens mitochondrial permeability transition pore by interacting with adenine nucleotide translocase (ANT) or voltage-dependent anion protein (VDAC), followed by cytosolic release of cytochrome c. In Sprague-Dawley rats, coimmunoprecipitation and Western blot analyses revealed sequential manifestations during endotoxemia of membrane-bound translocation of PKC, dissociation of cytosolic PKC/Bax complex, mitochondrial translocation of activated Bax, augmented Bax/ANT or Bax/VDAC association, elevated cytosolic cytochrome c and caspase 3, and DNA fragmentation in ventrolateral medulla. Microinjection of iNOS inhibitor into bilateral RVLM significantly retarded PKC and Bax activation. The induced association of translocated Bax with ANT or VDAC and the triggered mitochondrial apoptotic signaling cascade were blunted by blockade in RVLM of PKC, mitochondrial translocation of Bax, Bax channels, ANT, or caspase 3, alongside significant amelioration of cardiovascular depression. We conclude that formation of mitochondrial Bax/ANT or Bax/VDAC complex that initiates caspase 3-dependent apoptosis in the RVLM as a result of PKC-dependent mitochondrial translocation of activated Bax activated by iNOS-derived NO plays a pivotal role in the manifestation of endotoxin-induced cardiovascular depression.
- Subjects :
- Animals
Apoptosis
Apoptosis Regulatory Proteins metabolism
Cardiovascular Diseases etiology
Caspase 3 physiology
Disease Models, Animal
Endotoxemia complications
Enzyme Activation
Medulla Oblongata pathology
Protein Transport
Rats
Rats, Sprague-Dawley
Endotoxemia physiopathology
Medulla Oblongata enzymology
Mitochondria metabolism
Nitric Oxide Synthase Type II metabolism
Protein Kinase C metabolism
bcl-2-Associated X Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0026-895X
- Volume :
- 71
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 17227955
- Full Text :
- https://doi.org/10.1124/mol.106.031161