Extracellular Superoxide Dismutase Protects Cardiomyocytes During Hyperoxia

<p>Reactive oxygen species are implicated in tissue damage in many cardiovascular diseases. The current study was designed to test the hypothesis that exposure to high inspired oxygen concentrations (100%) damages cardiac mitochondria and that a biogenic response is needed for cell survival. The study was done in mice with a transgene (TG) for extracellular superoxide dismutase (EC-SOD) or with the EC-SOD gene knockout (KO). Adult EC-SOD mice and their wild type littermates and EC-SOD KO mice and their wild type littermates were exposed to 100% oxygen for 6 hours and for 72 hours, and the hearts were subsequently removed under deep anesthesia. The mortality rate in KO mice after 72 hours (25%) was significantly higher than wild type littermates (10%) and TG mice (4.2%). In the EC-SOD TG mice, 6 hours of exposure to hyperoxia activated the transcription of nuclear genes important for mitochondrial biogenesis---nuclear respiratory factors (NRF-1 and NRF-2) and their co-regulator PGC-1α---leading to expression of mitochondrial transcription factor A (Tfam), which regulates mitochondrial transcription and replication. Hyperoxia also induced activation of NRF-1 and NRF-2 in EC-SOD KO mice after 6 hours but down-regulated Tfam and PGC1α transcripts. But after 72 hours, mRNA expression for NRF-2, PGC-1α and Tfam increased in these mice.</p> <p>The protein expression of the pro-survival Protein Kinase B (Akt) was significantly increased by hyperoxia in the TG hearts after 6 hours (<em>p</em>pp</p> <p>In conclusion, systemic hyperoxia consistently increases mitochondrial biogenesis markers in the mouse heart, most prominently in EC-SOD TG mice, and co-incidentally with increases in Akt, p-Bad and p-GSK-3 R. This suggests that extracellular reactive oxygen products activate mitochondrial biogenesis and the pro-survival pathway in TG mice. Also, hyperoxia decreased the activation of Tfam and PGC-1α transcription after 6 hours and increased it again after 72 hours in KO mice. This was associated with a decrease in expression of Akt, p-Bad and p-GSK-3β and an increase in p38, indicating that either hyperoxia activated mitochondrial biogenesis and pro-survival pathways through p38 or that hyperoxia produced more oxidative damage to the mitochondria in the KO. In the latter case, the increase in p38 may be a signal for activation of apoptotic pathways.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Year dc:date.available

2006

Author dc:creator

• Ali, Mervat Elsayed

Contributors dc:contributor

• Frank J. Castora
• Claude A. Piantadosi
• Miriam D. Rosenthal
• Hajer B. Suliman
• Peter F. Blackmore

• Cardiomyocytes
• Hyperoxia
• Superoxide dismutase
• Molecular Biology

Identifier

9781109910483

OAI identifier oai:identifier

oai:digitalcommons.odu.edu:biomedicalsciences_etds-1002