Cyclophilin A inhibition as potential treatment of human aortic valve calcification

Research output: Contribution to journalArticlepeer-review

Abstract

Aortic valve stenosis (AS) is a pathological condition that affects about 3% of the population, representing the most common valve disease. The main clinical feature of AS is represented by the impaired leaflet motility, due to calcification, which leads to the left ventricular outflow tract obstruction during systole. The formation and accumulation of calcium nodules are driven by valve interstitial cells (VICs). Unfortunately, to date, the in vitro and in vivo studies were not sufficient to fully recapitulate all the pathological pathways involved in AS development, as well as to define a specific and effective pharmacological treatment for AS patients. Cyclophilin A (CyPA), the most important immunophilin and endogenous ligand of cyclosporine A (CsA), is strongly involved in several detrimental cardiovascular processes, such as calcification. To date, there are no data on the CyPA role in VIC-mediated calcification process of AS. Here, we aimed to identify the role of CyPA in AS by studying VIC calcification, in vitro. In this study, we found that (i) CyPA is up-regulated in stenotic valves of AS patients, (ii) pro-calcifying medium promotes CyPA secretion by VICs, (iii) in vitro treatment of VICs with exogenous CyPA strongly stimulates calcium deposition, and (iv) exogenous CyPA inhibition mediated by CsA analogue MM284 abolished in vitro calcium potential. Thus, CyPA represents a biological target that may act as a novel candidate in the detrimental AS development and its inhibition may provide a novel pharmacological approach for AS treatment.

Original languageEnglish
Article number104888
JournalPharmacological Research
Volume158
DOIs
Publication statusPublished - Aug 2020

Keywords

  • Aortic valve stenosis
  • Calcification
  • Cyclophilin A
  • Cyclosporin A analogue
  • Pharmacological target

ASJC Scopus subject areas

  • Pharmacology

Fingerprint Dive into the research topics of 'Cyclophilin A inhibition as potential treatment of human aortic valve calcification'. Together they form a unique fingerprint.

Cite this