Cyclophilin A, a novel extracellular link in non-ischemic adverse remodelling?

Myocardial remodelling, characterised by alterations in cardiomyocyte structure and the development of fibrosis, is a key process driving cardiac hypertrophy (1). These changes contribute to increased myocardial stiffness, which plays a significant role in the onset of diastolic dysfunction and, ultimately, heart failure. When it comes to cardiac fibrosis, beyond the extent of collagen deposition, the degree of collagen cross-linking is equally crucial, as it increases fibres stiffness and makes them more resistant to degradation. Increased collagen cross-linking has been associated with increased myocardial stiffness, diastolic dysfunction and poor outcomes in heart failure patients (2). Notably, over a decade ago, Professors Paulus and Tschöpe highlighted inflammation as a central factor in the progression of diastolic dysfunction and heart failure with preserved ejection fraction (3).  Despite the recognised significance of fibrosis and cardiomyocyte hypertrophy in non-ischaemic, non-inflammatory heart disease, therapeutic options remain limited. There is an urgent need to deepen our understanding of the mechanisms involved and to develop novel therapies that specifically target myocardial fibrosis without disrupting the physiological collagen network.

In the current paper (4), Sigle and col. focus on the study of cyclophilin A, an immunophilin with divergent intracellular and extracellular effects (5). When secreted, it interacts with its receptor EMMPRIN, and exerts proinflammatory and profibrotic effects. In this elegant study the authors follow a multidisciplinary approach combining studies in human samples and experimental in vitro and in vivo models of angiotensin II-induced cardiac remodelling to delve into the pathophysiological mechanisms mediated by extracellular cyclophilin A. Elevated cyclophilin A in cardiac samples from patients with non-ischaemic, non-inflammatory heart failure was associated with inflammation and with adverse clinical outcome. The role of extracellular cyclophilin A in driving cardiac hypertrophy and fibrosis was further validated in a mouse model subjected to angiotensin II infusion. Importantly, the authors develop a neutralising antibody that selectively blocks extracellular cyclophilin A, which successfully attenuated fibrosis, hypertrophy, and inflammation in this model, while also reducing myocardial stiffness.

A particularly innovative aspect of this study is the use of Raman spectromics, a cutting-edge, label-free technique that offers insights into the biochemical composition of tissue samples, allowing the assessment of molecular changes. This approach enabled the identification of alterations in myosin conformation and collagen cross-linking, both of which contribute to increased tissue stiffness.

In conclusion, this study uncovers a novel mechanism linking inflammation to cardiac remodeling in non-ischaemic heart disease. Extracellular cyclophilin A emerges as a promising therapeutic target for addressing myocardial remodelling in conditions such as hypertension. Further research is needed to determine whether blocking extracellular cyclophilin A not only prevents myocardial remodeling but also facilitates reverse remodelling in heart failure.