Targeting Cyclophilin A in the Cardiac Microenvironment Preserves Heart Function and Structure in Failing Hearts

Area of Science:

• Cardiovascular Research
• Molecular Cardiology
• Immunology

Background:

• Cardiac hypertrophy involves myocardial remodeling, impacting contractility and leading to heart failure.
• Extracellular signaling molecules, including extracellular cyclophilin A (eCyPA), are implicated in cardiac hypertrophy pathogenesis.
• CyPA is identified as a key factor in the development of cardiac dysfunction.

Purpose of the Study:

• To investigate the role of eCyPA in myocardial dysfunction and cardiac remodeling.
• To evaluate the therapeutic potential of inhibiting extracellular CyPA accumulation in heart failure.

Main Methods:

• Utilized a multidisciplinary approach with in silico, in vitro, in vivo, and ex vivo studies.
• Analyzed human heart tissue from heart failure patients and a mouse model of angiotensin II-induced heart failure.
• Assessed eCyPA inhibition using a neutralizing anti-eCyPA monoclonal antibody.

Main Results:

• Significant eCyPA accumulation observed in human and murine failing hearts.
• Higher eCyPA levels correlated with poor clinical outcomes and impaired cardiac contractility.
• Inhibition of eCyPA prevented angiotensin II-induced myocardial remodeling and dysfunction in mice.

Conclusions:

• eCyPA plays a pathogenic role in cardiac remodeling, myocardial stiffening, and heart failure.
• Antibody-based inhibition of eCyPA presents a potential novel therapeutic strategy for nonischemic heart failure.
• Further research is warranted to explore the translational potential in human patients.