Modulation of mitochondrial complex I during reperfusion reduces cardiac injury. Complex I exists in two structural states: active (A) and deactive (D) with transition from A→D during ischemia. Reperfusion reactivates D→A with an increase in ROS production. Metformin preserves the D-Form. Our aim was to study the contribution of maintenance of deactivation of complex I during early reperfusion by metformin to protect against ischemia reperfusion injury. Our results showed that metformin decreased H9c2 cardiomyoblast apoptosis and total cell death following simulated ischemia for six hours followed by reoxygenation for twenty four hours compared to untreated cells. Reactive oxygen species (ROS) generation was reduced at the onset of reoxygenation with metformin treatment. Metformin also prevented the acute reactivation of complex I during reoxygenation following 10 minutes of hypoxia accompanied by decreased ROS generation. In addition, the content of C/EBP homologous protein was decreased in metformin treated cells, suggesting that metformin treatment decreased endoplasmic reticulum stress. 5' adenosine monophosphate-activated protein kinase was activated in our model independent of metformin treatment. Intriguingly, metformin protects in 5' adenosine monophosphate-activated protein kinase knock down system. Surprisingly, we found that metformin successfully downregulated p53 compared to untreated simulated ischemia reoxygenation. We sought potential metformin related impact on anti-apoptotic protein B-cell lymphoma 2. Our results showed the expression of the anti-apoptotic protein B-cell lymphoma 2 was markedly decreased in SI6/RO24 and metformin increased expression of B-cell lymphoma 2. Metformin, likely by partial inhibition of complex I with decreased ROS generation, resulted in less sulfhydryl modification and decreased modification of thiol groups by nitrosylation.
We propose that the slowing down of activation of complex I at early stage of reperfusion by acute use of high dose metformin would be protective in cells and hearts against ischemia reperfusion injury. This potential new mechanism of protection is relevant at the onset of reperfusion to directly modulate electron transport to achieve cardiac protection and to decrease cardiac cell injury.
Modulation of mitochondrial complex I during reperfusion reduces cardiac injury. Complex I exists in two structural states: active (A) and deactive (D) with transition from A→D during ischemia. Reperfusion reactivates D→A with an increase in ROS production. Metformin preserves the D-Form. Our aim was to study the contribution of maintenance of deactivation of complex I during early reperfusion by metformin to protect against ischemia reperfusion injury. Our results showed that metformin decreased H9c2 cardiomyoblast apoptosis and total cell death following simulated ischemia for six hours followed by reoxygenation for twenty four hours compared to untreated cells. Reactive oxygen species (ROS) generation was reduced at the onset of reoxygenation with metformin treatment. Metformin also prevented the acute reactivation of complex I during reoxygenation following 10 minutes of hypoxia accompanied by decreased ROS generation. In addition, the content of C/EBP homologous protein was decreased in metformin treated cells, suggesting that metformin treatment decreased endoplasmic reticulum stress. 5' adenosine monophosphate-activated protein kinase was activated in our model independent of metformin treatment. Intriguingly, metformin protects in 5' adenosine monophosphate-activated protein kinase knock down system. Surprisingly, we found that metformin successfully downregulated p53 compared to untreated simulated ischemia reoxygenation. We sought potential metformin related impact on anti-apoptotic protein B-cell lymphoma 2. Our results showed the expression of the anti-apoptotic protein B-cell lymphoma 2 was markedly decreased in SI6/RO24 and metformin increased expression of B-cell lymphoma 2. Metformin, likely by partial inhibition of complex I with decreased ROS generation, resulted in less sulfhydryl modification and decreased modification of thiol groups by nitrosylation.
We propose that the slowing down of activation of complex I at early stage of reperfusion by acute use of high dose metformin would be protective in cells and hearts against ischemia reperfusion injury. This potential new mechanism of protection is relevant at the onset of reperfusion to directly modulate electron transport to achieve cardiac protection and to decrease cardiac cell injury.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-6645 |
| Date | 01 January 2018 |
| Creators | Mohsin, Ahmed Abdul Hussein |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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