Blocking caspase-activated apoptosis improves contractility in failing myocardium

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Cardiac myocyte apoptosis is present in end-stage human heart failure.
• The therapeutic benefit of inhibiting apoptosis in congestive heart failure (CHF) remains unclear.
• Caspase activation's role in cardiac contractility and sarcomere organization in CHF needs further investigation.

Purpose of the Study:

• To investigate the role of caspase activation in cardiac contractility and sarcomere organization during the development of congestive heart failure (CHF).
• To determine the therapeutic utility of blocking apoptosis in a rabbit model of heart failure.

Main Methods:

• Utilized a rabbit model of heart failure induced by rapid ventricular pacing.
• Employed in vivo transcoronary adenovirus-mediated gene delivery of the caspase inhibitor p35.
• Assessed cardiac function, caspase activity, DNA-histone formation, and sarcomere organization in vitro and in vivo.

Main Results:

• Caspase activation was linked to reduced myocyte contractile force and sarcomeric destruction in failing hearts.
• Gene transfer of p35 inhibited caspase 3 activity and DNA-histone formation, improving left ventricular pressure and decreasing LVEDP.
• In vitro, caspase 3 microinjection into myocytes caused sarcomeric disorganization and reduced contractility.

Conclusions:

• Caspase activation directly impairs cardiac function by disrupting sarcomere structure.
• Inhibiting caspases with p35 demonstrates a therapeutic benefit in a heart failure model.
• These findings suggest novel therapeutic strategies targeting antiapoptotic regimens for congestive heart failure.