Ventricular myocyte caspases are directly responsible for endotoxin-induced cardiac dysfunction

Area of Science:

• Cardiology
• Molecular Biology
• Cell Biology

Background:

• Sepsis-induced apoptosis is often linked to lymphocyte death.
• Caspase activation may directly impair organ system cell function.
• The study investigates caspase activation in left ventricular (LV) cardiomyocytes during sepsis.

Purpose of the Study:

• To determine if left ventricular (LV) cardiomyocyte caspase activation directly contributes to sepsis-induced heart contractile dysfunction.
• To explore the molecular mechanisms linking sepsis to cardiac dysfunction at the cellular level.

Main Methods:

• Isolated LV cardiomyocytes from endotoxin-injected rats were analyzed for contractile function and caspase activity.
• Western blotting and enzymatic assays were used to assess caspase activation and myofilament cleavage.
• Inhibition of caspases using zVAD.fmk and zDEVD.cmk was employed in vivo and in vitro.

Main Results:

• Endotoxin injection in rats led to reduced LV cardiomyocyte contractile reserve and myofilament response to calcium.
• Increased caspase-3, -8, and -9-like activities were observed in LV cardiomyocytes, correlating with sarcomere destruction and troponin T cleavage.
• Treatment with zVAD.fmk prevented sepsis-induced LV cardiomyocyte dysfunction, sarcomere damage, and troponin T cleavage.
• Serum from endotoxin-treated rats induced contractile dysfunction and caspase activation in naive cardiomyocytes, effects blocked by caspase inhibitors.

Conclusions:

• A significant link exists between endotoxin-induced caspase activation and impaired contractile reserve in LV cardiomyocytes.
• Caspase activation directly contributes to sarcomere disarray and functional decline in sepsis-related heart dysfunction.