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Burn-Induced Cardiac Mitochondrial Dysfunction via Interruption of the PDE5A-cGMP-PKG Pathway
Jake J Wen1, Claire B Cummins1, Ravi S Radhakrishnan1
1Division of Pediatric Surgery, Department of Surgery, University of Texas Medical Branch, Galveston, TX 77555, USA.
Abstract:
Burn-induced heart dysfunction is a key factor for patient mortality. However, the molecular mechanisms are not yet fully elucidated. This study sought to understand whether burn-induced heart dysfunction is associated with cardiac mitochondrial dysfunction and interruption of the PDE5A-cGMP-PKG pathway. Sixty percent total body surface area (TBSA) scald burned rats (±sildenafil) were used in this study. A transmission electron microscope (TEM), real-time qPCR, O2K-respirometer, and electron transport chain assays were used to characterized molecular function. Cardiac mitochondrial morphological shapes were disfigured with a decline in mitochondrial number, area, and size, resulting in deficiency of cardiac mitochondrial replication. Burn induced a decrease in all mitDNA encoded genes. State 3 oxygen consumption was significantly decreased. Mitochondrial complex I substrate-energized or complex II substrate-energized and both of respiratory control ratio (RCRs) were decreased after burn. All mitochondrial complex activity except complex II were decreased in the burn group, correlating with decreases in mitochondrial ATP and MnSOD activity. Sildenafil, a inhibitor of the PDE5A-cGMP-PKG pathway, preserved the mitochondrial structure, respiratory chain efficiency and energy status in cardiac tissue. Furthermore, sildenafil treatment significantly restored ADP-conjugated respiration in burned groups. In conclusion, cardiac mitochondrial damage contributes to burn-induced heart dysfunction via the PDE5A-cGMP-PKG pathway.
Insights
Severe burns cause heart dysfunction by damaging cardiac mitochondria and disrupting the PDE5A-cGMP-PKG pathway. Sildenafil treatment protected heart function by preserving mitochondrial integrity and energy status.
Area of Science:
- Cardiovascular Science
- Mitochondrial Biology
- Burn Medicine
Background:
- Burn-induced heart dysfunction is a significant cause of mortality.
- The precise molecular mechanisms underlying this cardiac dysfunction remain unclear.
- Investigating the role of mitochondrial function and specific signaling pathways is crucial.
Purpose of the Study:
- To investigate the association between burn-induced heart dysfunction and cardiac mitochondrial dysfunction.
- To determine the involvement of the phosphodiesterase type 5 A (PDE5A)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway in burn injury.
- To evaluate the therapeutic potential of sildenafil, a PDE5A inhibitor, in mitigating burn-induced cardiac damage.
Main Methods:
- Utilized a rat model of severe scald burn (60% total body surface area).
- Employed transmission electron microscopy (TEM), real-time quantitative polymerase chain reaction (qPCR), O2K-respirometry, and electron transport chain assays.
- Assessed cardiac mitochondrial morphology, replication, gene expression, respiratory capacity, and enzyme activities.
Main Results:
- Burn injury led to disfigured mitochondrial morphology, reduced mitochondrial number and size, and impaired mitochondrial replication.
- Significant decreases in mitochondrial DNA (mtDNA)-encoded genes, State 3 oxygen consumption, and respiratory control ratios (RCRs) were observed.
- Activities of mitochondrial complexes (except Complex II), ATP production, and manganese superoxide dismutase (MnSOD) were reduced post-burn.
- Sildenafil treatment preserved mitochondrial structure, improved respiratory chain efficiency, maintained energy status, and restored ADP-conjugated respiration.
Conclusions:
- Cardiac mitochondrial damage is a key contributor to burn-induced heart dysfunction.
- The PDE5A-cGMP-PKG pathway plays a critical role in mediating these effects.
- Sildenafil demonstrates a protective effect against burn-induced cardiac mitochondrial dysfunction and subsequent heart dysfunction.
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