PKCδ causes sepsis-induced cardiomyopathy by inducing mitochondrial dysfunction

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Sepsis Pathophysiology

Background:

• Sepsis-induced cardiomyopathy (SIC) significantly increases patient mortality.
• Existing treatments for SIC are limited, necessitating the identification of underlying mechanisms.
• Previous research indicates elevated reactive oxygen species (ROS) and mitochondrial dysfunction in SIC.

Purpose of the Study:

• To investigate the role of protein kinase C delta (PKCδ) in SIC.
• To determine if PKCδ is essential for abnormal calcium handling and mitochondrial dysfunction during sepsis.
• To evaluate the protective effects of genetic deletion of PKCδ against SIC.

Main Methods:

• Polymicrobial sepsis was induced using cecal ligation and puncture (CLP) in wild-type (WT) and PKCδ knockout (KO) mice.
• Cardiac function, including ejection fraction and cardiomyocyte contractility, was assessed.
• Calcium handling, ryanodine receptor-2 oxidation, mitochondrial ROS production, and mitochondrial membrane potential were measured.

Main Results:

• CLP surgery reduced ejection fraction in WT mice but not in PKCδ KO mice.
• WT cardiomyocytes exposed to lipopolysaccharide (LPS) showed impaired contractility and calcium transients, unlike PKCδ KO cardiomyocytes.
• PKCδ deletion prevented LPS-induced increases in cellular ROS and mitochondrial dysfunction, including altered morphology and decreased membrane potential.

Conclusions:

• PKCδ is critically involved in the pathophysiology of sepsis-induced cardiomyopathy.
• PKCδ promotes cardiac dysfunction by generating ROS and inducing mitochondrial damage.
• Targeting PKCδ offers a potential therapeutic strategy for protecting the heart during sepsis.