PKCδ causes sepsis-induced cardimyopathy by inducing mitochondrial dysfunction

Authors

Leroy C. Joseph, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York
Michael V. Reyes, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York
Kundanika R. Lakkadi, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York
Blake H. Gowen, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York
Gyorgy Hasko, Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York
Konstantinos Drosatos, Metabolic Biology Laboratory, Center for Translational Medicine, Department of Pharmacology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
John P. Morrow, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York

Document Type

Article

Publication Date

4-1-2020

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.

Recommended Citation

Joseph LC, Reyes MV, Lakkadi KR, Gowen BH, Hasko G, Drosatos K, Morrow JP. PKCδ causes sepsis-induced cardiomyopathy by inducing mitochondrial dysfunction. Am J Physiol Heart Circ Physiol. 2020 Apr 1;318(4):H778-H786. doi: 10.1152/ajpheart.00749.2019. Epub 2020 Mar 6. PMID: 32142354; PMCID: PMC7191496.