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

Abstract

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.

• Authors: Henry Dube, David Selwood, Sylvanie Malouitre, Michela Capano, Michela I Simone, Martin Crompton
• Journal: The Biochemical journal (Biochem J) Vol. 441 Issue 3 Pg. 901-7 (Feb 01 2012) ISSN: 1470-8728 [Electronic] England
• PMID: 22035570 (Publication Type: Evaluation Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclophilin D
• Cyclosporine
• Cyclophilins

Topics

• Animals
• Cells, Cultured
• Cyclophilin D
• Cyclophilins (antagonists & inhibitors, metabolism)
• Cyclosporine (administration & dosage, pharmacology)
• Cytoprotection (drug effects)
• Drug Delivery Systems
• Drug Evaluation, Preclinical
• Mitochondria, Heart (drug effects, metabolism, pathology)
• Models, Biological
• Myocardial Reperfusion Injury (metabolism, pathology, prevention & control)
• Myocytes, Cardiac (drug effects, metabolism)
• Protein Binding
• Rats
• Rats, Sprague-Dawley
• Substrate Specificity (drug effects)