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Circulating Factors Induce Cardiomyopathy after Burn Injury
Susana Fortich1, Jake J Wen1, Jana E Dejesus1
1From the Departments of Surgery (Fortich, Wen, Dejesus, and RS Radhakrishnan), University of Texas Medical Branch, Galveston, TX.
Insights
Burn injury releases circulating factors that damage heart cells and mitochondria. Sildenafil (SIL) treatment reversed this damage in vitro, suggesting a therapeutic potential for burn-induced cardiac dysfunction.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Burn Injury Pathophysiology
Background:
- Burn injury can lead to cardiac dysfunction via the phosphodiesterase type 5 (PDE5)-cyclic guanosine monophosphate-protein kinase G pathway.
- The role of circulating factors in post-burn cardiac damage and the potential of PDE5A inhibitors in vitro remain unclear.
Purpose of the Study:
- To investigate if circulating factors from burn injury cause mitochondrial damage in cardiomyocytes in vitro.
- To determine if PDE5A inhibitors can reverse this damage.
Main Methods:
- Human cardiomyocyte cell line (AC16) treated with serum from sham-injured rats, 24-hour post-burn (24hpb) rats, sildenafil (SIL) alone, or 24hpb serum with SIL.
- Analyses included ELISA, mitochondrial function assays, fluorescence microscopy, gene analysis, and Illumina RNA sequencing.
Main Results:
- 24hpb serum decreased cyclic guanosine monophosphate and increased cTN1 levels; SIL treatment reversed these changes.
- 24hpb serum induced cardiomyocyte cytotoxicity, apoptosis, and mitochondrial dysfunction (decreased ATP, impaired respiration).
- SIL treatment restored cardiomyocyte viability and mitochondrial function to near sham levels.
Conclusions:
- Circulating factors released post-burn injury contribute to cardiomyocyte mitochondrial damage.
- Sildenafil demonstrates potential in reversing burn-induced cardiac dysfunction by protecting mitochondria and improving cellular function in vitro.
Background:
Previous in vivo work has demonstrated that the phosphodiesterase type 5 (PDE5)-cyclic guanosine monophosphate-protein kinase G pathway is involved in burn-induced heart dysfunction. PDE5A inhibitors may reverse this dysfunction. It is unknown if circulating factors after burn injury can continue to damage cardiomyocytes and if this can be reversed by PDE5A inhibitors in vitro. This study hypothesized that circulating factors released after burn injury cause mitochondrial damage in cardiomyocytes in vitro.
Study Design:
Human cardiomyocyte cell line-AC16-was divided into 4 groups, which were treated with serum obtained from rats with sham injury, 24 hours post burn (24hpb), sildenafil (SIL) alone, and 24hpb treated with SIL. ELISA, mitochondrial function studies, fluorescence microscopy, gene analysis, and Illumina RNA sequencing were performed. GraphPad Prism 9.2.0 was used for statistical analysis.
Results:
Cyclic guanosine monophosphate levels were significantly decreased, and cTN1 levels were significantly increased in the 24hpb serum group. Treatment with SIL completely reversed this change, similar to our previous in vivo work. We observed that there was significantly decreased cell viability and cell proliferation and increased cell cytotoxicity, cell apoptosis, and cell reactive oxygen species production in the cells treated with 24hpb serum. Cells treated with 24hpb serum exhibited mitochondrial dysfunction, as demonstrated by decreased ATP production and compromised mitochondrial membrane integrity or potential, along with increased mitochondrial reactive oxygen species. Seahorse and O2K approaches confirmed 24hpb serum treated cardiomyocyte mitochondrial dysfunction as evidenced by decreases in mitochondrial basal respiration, proton leak, ATP production, and maximal respiration. SIL returned these responses to near sham levels.
Conclusions:
This study provided data that may improve the understanding of mechanisms driving cardiac dysfunction after burn injury. Our study provided evidence for understanding the pathogenic mechanism of circulating factors released after burn injury.
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