Sepsis-Induced Cardiomyopathy is Caused by Mitochondrial Dysfunction Due to Protein Kinase C (PKC) Delta Activation

Objective: Sepsis-induced cardiomyopathy (SIC) is a frequent complication of sepsis that is associated with increased mortality. There are no effective therapies. Oxidative stress and mitochondrial dysfunction are part of the pathophysiology of SIC but the upstream molecular pathways involved are unclear. Methods: We used PKCdelta knock-out (KO) mice and WT littermates for surgically-induced polymicrobial sepsis from cecal ligation and puncture (CLP). Isolated cardiomyocytes were used to evaluate oxidative stress, mitochondrial function, contractility, and calcium transients. Results: PKCdelta is activated in cardiomyocytes in sepsis models. In vivo, PKCdelta KO mice do not have decreased systolic function after sepsis, unlike WT littermates. WT cardiomyocytes show increased mitochondrial oxidative stress, partial depolarization of the mitochondrial inner membrane, decreased contractility, and decreased calcium transient amplitude. PKCdelta KO cardiomyocytes are protected from all of these abnormalities. Further, mitotempo improves contractility and calcium transients in WT cardiomyocytes, supported the role of mitochondrial dysfunction as a mechanism of SIC. Conclusion: PKDdelta KO mice are protected from SIC. Cardiomyocyte experiments indicate that mitochondrial dysfunction promotes oxidative stress and a decrease in contractility during sepsis. Translational impact: PKCdelta inhibition could be effective treatment for SIC.