Nitric oxide- and superoxide-dependent mitochondrial signaling in endotoxin-induced apoptosis in the rostral ventrolateral medulla of rats.
This study evaluated the hypothesis that the repertoire of cellular events that underlie circulatory fatality during endotoxemia may entail mitochondrial respiratory enzyme dysfunction, followed by the release of cytochrome c to the cytosol that triggers the activation of caspase cascades, leading to apoptotic cell death in the rostral ventrolateral medulla (RVLM) where sympathetic premotor neurons responsible for maintaining vasomotor tone are located. In adult Sprague-Dawley rats maintained under propofol anesthesia, nucleosomal DNA fragmentation was detected in the RVLM in a temporal profile that coincided positively with the progression of cardiovascular depression during experimental endotoxemia induced by Escherichia coli lipopolysaccharide (LPS). LPS also induced nitric oxide (NO) and superoxide (O(2)(-)) production, depressed mitochondrial Complex I and IV activity, promoted the release of cytochrome c from mitochondria to cytosol, upregulated the cytosolic expression of activated caspase-9 and -3, or increased caspase-3 enzyme activity in the RVLM. Microinjection bilaterally into the RVLM of an inducible nitric oxide synthase (iNOS) blocker, S-methylisothiourea, or a superoxide dismutase mimetic, Tempol, significantly blunted these apoptotic cellular events and antagonized the cardiovascular depression during endotoxemia. We conclude that caspase-dependent apoptotic cell death that results from NO- and O(2)(-)-associated mitochondrial signaling in the RVLM may underlie fatal cardiovascular depression during endotoxemia.
Chan
Samuel H H
SH
Center for Neuroscience, National Sun Yat-sen University, Kaohsiung 804, Taiwan, Republic of China.
Wu
Kay L H
KL
Wang
Ling-Lin
LL
Chan
Julie Y H
JY
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D053938:DNA Fragmentation; D004731:Endotoxins / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D009566:Nitrates / Q000737:chemistry; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000737:chemistry; D009707:Nucleosomes / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
D003497:Cyclic N-Oxides; D004731:Endotoxins; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D009707:Nucleosomes; D013113:Spin Labels; D013481:Superoxides; D007550:Isothiuronium; D009569:Nitric Oxide; D045304:Cytochromes c; D004247:DNA; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; C505410:Casp3 protein, rat; C506435:Casp9 protein, rat; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; C027744:S-methylisothiopseudouronium; D010100:Oxygen; C001803:tempol