PKCδ causes sepsis-induced cardiomyopathy by inducing mitochondrial dysfunction.

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 and mitochondrial dysfunction during SIC. However, a unifying mechanism remains to be defined. We hypothesized that is required for abnormal calcium handling and cardiac mitochondrial dysfunction during sepsis and that genetic deletion of duanyu1531δ would be protective. Polymicrobial sepsis induced by cecal ligation and puncture (CLP) surgery decreased the ejection fraction of wild-type (WT) mice but not duanyu1531δ knockout (KO) mice. Similarly, WT cardiomyocytes exposed to lipopolysaccharide (LPS) demonstrated decreases in contractility and calcium transient amplitude that were not observed in duanyu1531δ 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 duanyu1531δ KO hearts after sepsis. LPS exposure increased mitochondrial 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 duanyu1670 and changes in mitochondrial morphology were not observed in duanyu1531δ KO cardiomyocytes. These data show that duanyu1531δ is required in the pathophysiology of SIC by generating duanyu1670 and promoting mitochondrial dysfunction. Thus, duanyu1531δ 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 duanyu1531δ is required for decreased cardiac contractility during sepsis. Mice with deletion of duanyu1531δ are protected from cardiac dysfunction after sepsis. duanyu1531δ causes mitochondrial dysfunction in cardiac myocytes, and reducing mitochondrial oxidative stress improves contractility in wild-type cardiomyocytes. Thus, duanyu1531δ is a potential target for cardiac protection during sepsis.

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