Burn-Induced Cardiac Mitochondrial Dysfunction via Interruption of the PDE5A-cGMP-PKG Pathway

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.

Sildenafil Recovers Burn-Induced Cardiomyopathy

“…PDE5A inhibition raises cGMP levels, leading to downstream effects on the heart and vasculature [31]. PDE5A inhibitors may also inhibit RhoA-Rho kinase [14]. In this study, sildenafil was seen to not only inhibit PDE5A, but also to affect PKG-regulated genes.…”

“…Our previous work has demonstrated that a burn induces cardiac mitochondrial damage, as evidenced by morphological changes on electron microscopy, cardiac mitochondrial replication deficiency, and decreased mitochondrial complex activity and oxygen consumption [14]. Interestingly, treatment with sildenafil preserved the mitochondrial structure, respiratory chain efficiency and energy status after a burn [14]. This previous work indicates that PDE5A inhibition could be beneficial in treating burn-induced heart dysfunction.…”

“…Previously published articles have shown that sildenafil is effective in numerous heart-related diseases, such as diabetes [24], Chagas disease [25], heart failure [26], hypertension [27] and burns [14]. Our previous work has demonstrated that a burn induces cardiac mitochondrial damage, as evidenced by morphological changes on electron microscopy, cardiac mitochondrial replication deficiency, and decreased mitochondrial complex activity and oxygen consumption [14]. Interestingly, treatment with sildenafil preserved the mitochondrial structure, respiratory chain efficiency and energy status after a burn [14].…”

“…In addition, PDE5A inhibitors, such as sildenafil, prolong the effect of NO and cGMP, causing increased vasodilation through decreased smooth muscle tone [12]. In our preliminary work, we observed that burn-induced cardiac mitochondrial dysfunction is modulated via the AMPK-SIRT1-PGC1α-NFE2L2 ARE pathway [13] and the cGMP-PKG pathway [14]. However, little is known regarding the specific role of the PDE5A-cGMP-PKG1α pathway in burn-induced cardiac dysfunction.…”

Pathological Responses of Cardiac Mitochondria to Burn Trauma

“…To date, few studies have been conducted to investigate burn-induced alterations of mitochondrial morphology in the heart. Dr. Wen and his colleagues showed a disruption of mitochondrial distribution and polymorphism of the mitochondrial ultrastructure with decreased mitochondrial number and size in rat hearts 24 h after burn [ 21 ]. The impaired mitochondrial morphology and structure led to reduced cardiac mitochondrial replication, reduced activity in the transport chains, and ATP deficiencies in cardiac tissue, as a response to burn [ 21 ].…”