Abstract:
Cardiac hypertrophy is characterized by remodeling of the myocardium, involving both alterations in the extracellular matrix (ECM) and changes in cardiomyocyte structure. These alterations critically impair the contractility and relaxation of the heart, ultimately progressing to heart failure. Emerging evidence suggests that extracellular signaling molecules play a central role in the pathogenesis of cardiac hypertrophy and remodeling. Among these, the immunophilin Cyclophilin A (CyPA) has been identified as a key mediator. In this study, we aimed to unravel the interplay between extracellular CyPA (eCyPA) and myocardial dysfunction and evaluate the therapeutic potential of inhibiting its extracellular accumulation to improve heart function.
Employing a multidisciplinary approach that combines in silico, in vitro, in vivo, and ex vivo techniques, we studied mouse models of heart failure alongside human heart specimens to decipher the interactions between CyPA and the cardiac microenvironment in both basic science and clinical settings. Myocardial expression of CyPA and the inflammatory transcriptome were analyzed in human cardiac tissue samples from patients with non-ischemic, non-inflammatory congestive heart failure (n=187) using immunohistology and NanoString® technology. These analyses were paralleled by a mouse model of Angiotensin (Ang II)-induced heart failure, which was assessed by functional (echocardiography), structural (immunohistology, atomic force microscopy) and biomolecular (Raman spectroscopy) analyses. The effect of inhibiting eCyPA in the cardiac microenvironment was evaluated using a newly developed neutralizing anti-eCyPA monoclonal antibody.
Our results demonstrated a significant accumulation of CyPA in the cardiac microenvironment of both human and murine failing hearts. Elevated eCyPA expression was associated with worse clinical outcomes in patients (P=0.043) and correlated with contractile dysfunction in mice (Pearson’s rho=-0.73). Moreover, myocardial eCyPA expression was strongly linked to increased myocardial hypertrophy, inflammation, fibrosis, stiffness, and overall cardiac dysfunction in vivo. Antibody-based inhibition of eCyPA effectively prevented Ang II-induced myocardial remodeling and dysfunction in mice.
This project provides strong evidence of the pathogenic role of eCyPA in myocardial remodeling, stiffening, and dysfunction in heart failure and heart failure progression. Our findings suggest that targeting eCyPA with antibody-based inhibition could represent a promising therapeutic strategy for treating non-ischemic heart failure. Further research is warranted to explore the translational potential of these interventions in human patients.
Cardiac remodeling