PKCδ causes sepsis-induced cardiomyopathy by inducing mitochondrial dysfunction

Abstract

Sepsis-induced cardiomyopathy (SIC) is associated with increased patient mortality. At present, there are no specific therapies for SIC. Previous studies have reported increased reactive oxygen species (ROS) and mitochondrial dysfunction during SIC. However, a unifying mechanism remains to be defined. We hypothesized that PKCδ is required for abnormal calcium handling and cardiac mitochondrial dysfunction during sepsis and that genetic deletion of PKCδ would be protective. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) surgery decreased the ejection fraction of wild-type (WT) mice but not PKCδ knockout (KO) mice. Similarly, WT cardiomyocytes exposed to lipopolysaccharide (LPS) demonstrated decreases in contractility and calcium transient amplitude that were not observed in PKCδ KO cardiomyocytes. LPS treatment decreased sarcoplasmic reticulum calcium stores in WT cardiomyocytes, which correlated with increased ryanodine receptor-2 oxidation in WT hearts but not PKCδ KO hearts after sepsis. LPS exposure increased mitochondrial ROS and decreased mitochondrial inner membrane potential in WT cardiomyocytes. This corresponded to morphologic changes consistent with mitochondrial dysfunction such as decreased overall size and cristae disorganization. Increased cellular ROS and changes in mitochondrial morphology were not observed in PKCδ KO cardiomyocytes. These data show that PKCδ is required in the pathophysiology of SIC by generating ROS and promoting mitochondrial dysfunction. Thus, PKCδ is a potential target for cardiac protection during sepsis. NEW & NOTEWORTHY Sepsis is often complicated by cardiac dysfunction, which is associated with a high mortality rate. Our work shows that the protein PKCδ is required for decreased cardiac contractility during sepsis. Mice with deletion of PKCδ are protected from cardiac dysfunction after sepsis. PKCδ causes mitochondrial dysfunction in cardiac myocytes, and reducing mitochondrial oxidative stress improves contractility in wild-type cardiomyocytes. Thus, PKCδ is a potential target for cardiac protection during sepsis.

Neferine Ameliorates Sepsis-Induced Myocardial Dysfunction Through Anti-Apoptotic and Antioxidative Effects by Regulating the PI3K/AKT/mTOR Signaling Pathway

“…Mitochondria play a vital role in maintaining the homeostasis of cardiomyocytes, which could be disrupted by excessive ROS. Accumulating evidence demonstrates that septic cardiomyopathy involves mitochondrial dysfunction (Chen et al, 2019;Stanzani et al, 2019;Joseph et al, 2020). Mitochondrial ROS are the driving force of mitochondrial dysfunction in septic cardiomyopathy (Joseph et al, 2020).…”

“…Accumulating evidence demonstrates that septic cardiomyopathy involves mitochondrial dysfunction (Chen et al, 2019;Stanzani et al, 2019;Joseph et al, 2020). Mitochondrial ROS are the driving force of mitochondrial dysfunction in septic cardiomyopathy (Joseph et al, 2020). Studies have found that in septic cardiomyopathy, mitochondrial dysfunction is a key contributor to impaired mitochondrial function and increased mitochondrial fission, leading ultimately to mitochondrial dysfunction and cardiomyocyte apoptosis (Haileselassie et al, 2019).…”

CircTLK1 modulates sepsis‐induced cardiomyocyte apoptosis via enhancing PARP1/HMGB1 axis–mediated mitochondrial DNA damage by sponging miR‐17‐5p

“…Oxidative stress has been considered as another player in the progression of septic cardiomyopathy. Previous studies showed that the excessive generation of ROS may cause oxidative stress damage to the mitochondria of cardiomyocytes during septic cardiomyopathy 12,42 . Multiple antioxidant enzymes (eg SOD) are crucial to protect against mitochondrial oxidative stress.…”

Sepsis-Associated Encephalopathy and Blood-Brain Barrier Dysfunction

“…A cytosolic protein, the inflammatory regulator protein kinase C-delta (PKCδ), is also involved in mediating BBB damage during SAE. PKCδ depletion in isolated cardiomyocytes was found to reduce ROS production and prevent changes in inner mitochondrial membrane potential after LPS treatment (20 ng/mL for 1 h) (25). In rats, CLP-induced PKCδ activation and BBB permeability, as evaluated by Evans Blue extravasation into the brain tissue, were attenuated by the treatment with a PKCδ peptide inhibitor, PKCδ-TAT (48).…”