Sildenafil Recovers Burn-Induced Cardiomyopathy

Wen, Julie; Cummins, Claire B.; Radhakrishnan, Ravi S.

doi:10.3390/cells9061393

Cited by 17 publications

(17 citation statements)

References 43 publications

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“…Some disease states predispose mitochondria to be more sensitive to disruption during preparation, and there are no bioenergetic living cell culture data with cardiomyocytes in a burn model. While our previous publication demonstrates some bioenergetic data [46][47] future study is needed to quantify tissue mitochondria.…”

Section: Discussionmentioning

confidence: 97%

The Genetic Evidence of Burn-Induced Cardiac Mitochondrial Metabolism Confusion

Wen¹,

Cummins²,

Williams³

et al. 2020

Preprint

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Burn-induced cardiac dysfunction is thought to involve mitochondrial dysfunction although the mechanisms responsible are unclear. In this study, we used our established model of in vivo burn injury to understand the genetic evidence of burn-induced mitochondrial metabolism confusion by describing cardiac mitochondrial metabolism-related gene expression after burn. Cardiac tissue was collected at 24 hours after burn injury. An O2K respirometer system was utilized to measure cardiac mitochondrial function. Oxidative phosphorylation complex activities were determined using enzyme activity assays. RT Profiler PCR array was used to identify differential regulation of genes involved in mitochondrial biogenesis and metabolism. Quantitative qPCR and Western Blotting were applied to validate differentially expressed genes. Burn-induced cardiac mitochondrial dysfunction was supported by the finding of decreased state 3 respiration and decreased mitochondrial electron transport chain activity in complex I, III, IV, and V following burn injury. Eighty-four mitochondrial metabolism-related gene profiles were measured. The mitochondrial gene profile showed that one third of genes related to mitochondrial energy and metabolism was differentially expressed. Of these 28 genes, 15 were more than 2-fold upregulated and 13 were more than 2-fold downregulated. All genes were validated using qPCR; 4 genes had a protein level which correlated with the observed change in gene expression. This study provides preliminary evidence that a large percentage of mitochondrial metabolism-related genes in cardiomyocytes were significantly affected by burn injury.

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Section: Discussionmentioning

confidence: 97%

The Genetic Evidence of Burn-Induced Cardiac Mitochondrial Metabolism Confusion

Wen¹,

Cummins²,

Williams³

et al. 2020

Preprint

Self Cite

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“…The damaged mitochondrial function in rat hearts was mediated through the phosphodiesterase 5 (PDE5)-cyclic GMP protein kinase G (cGMP-PKG) pathway, while blockade of this signaling by sildenafil treatment reversed burn-induced mitochondrial damage [ 21 ]. Severe burn injury significantly increased PDE5A expression (both protein and mRNA), decreased cGMP levels, and reduced PKG protein level and activity in rat hearts [ 26 ]. Treatment of sildenafil, an inhibitor of PDE5, normalized myocardial levels of PDE5A, cGMP, and PKG, as well as PKG activity after a burn [ 26 ].…”

Section: Burn Trauma-damaged Cardiac Mitochondriamentioning

confidence: 99%

“…Severe burn injury significantly increased PDE5A expression (both protein and mRNA), decreased cGMP levels, and reduced PKG protein level and activity in rat hearts [ 26 ]. Treatment of sildenafil, an inhibitor of PDE5, normalized myocardial levels of PDE5A, cGMP, and PKG, as well as PKG activity after a burn [ 26 ]. Indeed, using sildenafil to increase cGMP levels improved cardiac mitochondrial morphology, mitochondrial DNA (mtDNA) replication, mtDNA-encoded gene expressions, and mitochondrial electron transport chain function, as well as mitochondrial complex activity in animal experiments [ 21 ].…”

Section: Burn Trauma-damaged Cardiac Mitochondriamentioning

confidence: 99%

“…It has been shown that burn injury did not affect the activity and expression of cytochrome-c oxidase in cardiac mitochondrial fractions, but led to mitochondrial loss of ROS defense, resulting in post-burn myocardial dysfunction in a rat model [ 28 ]. In fact, burn injury dysregulates antioxidant gene expression, leading to declines of total antioxidants, total superoxide dismutase (SOD) activity, and MnSOD activity in rat hearts after burn [ 26 ]. Burn-caused mitochondrial damage in mouse heart tissue also correlated with ROS accumulation and increased oxidative stress [ 29 ].…”

Section: Burn Trauma-damaged Cardiac Mitochondriamentioning

confidence: 99%

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Pathological Responses of Cardiac Mitochondria to Burn Trauma

Wang

Scott

Koniaris

et al. 2020

IJMS

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Despite advances in treatment and care, burn trauma remains the fourth most common type of traumatic injury. Burn-induced cardiac failure is a key factor for patient mortality, especially during the initial post-burn period (the first 24 to 48 h). Mitochondria, among the most important subcellular organelles in cardiomyocytes, are a central player in determining the severity of myocardial damage. Defects in mitochondrial function and structure are involved in pathogenesis of numerous myocardial injuries and cardiovascular diseases. In this article, we comprehensively review the current findings on cardiac mitochondrial pathological changes and summarize burn-impaired mitochondrial respiration capacity and energy supply, induced mitochondrial oxidative stress, and increased cell death. The molecular mechanisms underlying these alterations are discussed, along with the possible influence of other biological variables. We hope this review will provide useful information to explore potential therapeutic approaches that target mitochondria for cardiac protection following burn injury.

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“…The authors use a model of diet-induced obesity and myoblasts in culture to study the deleterious effects of high fat diet on cardiac function, and to show that antioxidants specifically targeted to mitochondria reduced cardiac oxidative stress and prevented cardiac damage. Sildenafil, an inhibitor of phosphodiesterase 5A (PDE5A), was also able to decrease the production of reactive oxygen species (ROS), fibrosis and inflammation, thereby recovering burn-induced cardiac dysfunction in a rat model [ 6 ].…”

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confidence: 99%