A mitochondrial-targeted cyclosporin A with high binding affinity for cyclophilin D yields improved cytoprotection of cardiomyocytes

• Published in: Biochemical journal Vol. 441; no. 3; p. 901
• Main Authors: Dube, Henry, Selwood, David, Malouitre, Sylvanie, Capano, Michela, Simone, Michela I, Crompton, Martin
• Format: Journal Article
• Language: English
• Published: England 01-02-2012
• Subjects: Animals; Cells, Cultured; Cyclophilins - antagonists & inhibitors; Cyclophilins - metabolism; Cyclosporine - administration & dosage; Cyclosporine - pharmacology; Cytoprotection - drug effects; Drug Delivery Systems; Drug Evaluation, Preclinical; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Mitochondria, Heart - pathology; Models, Biological; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - prevention & control; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Peptidyl-Prolyl Isomerase F; Protein Binding; Rats; Rats, Sprague-Dawley; Substrate Specificity - drug effects
• ISSN: 1470-8728
• DOI: 10.1042/BJ20111301

Mitochondrial CyP-D (cyclophilin-D) catalyses formation of the PT (permeability transition) pore, a key lesion in the pathogenesis of I/R (ischaemia/reperfusion) injury. There is evidence [Malouitre, Dube, Selwood and Crompton (2010) Biochem. J. 425, 137-148] that cytoprotection by the CyP inhibitor CsA (cyclosporin A) is improved by selective targeting to mitochondria. To investigate this further, we have developed an improved mtCsA (mitochondrial-targeted CsA) by modifying the spacer linking the CsA to the TPP+ (triphenylphosphonium) (mitochondrial-targeting) cation. The new mtCsA exhibits an 18-fold increase in binding affinity for CyP-D over the prototype and a 12-fold increase in potency of inhibition of the PT in isolated mitochondria, owing to a marked decrease in non-specific binding. The cytoprotective capacity was assessed in isolated rat cardiomyocytes subjected to transient glucose and oxygen deprivation (pseudo-I/R). The new mtCsA was maximally effective at lower concentrations than CsA (3-15 nM compared with 50-100 nM) and yielded improved cytoprotection for up to 3 h following the pseudo-ischaemic insult (near complete compared with 40%). These data indicate the potential value of selective CyP-D inhibition in cytoprotection.