Cyclosporin A binding to mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury

1997 ◽  
pp. 167-172 ◽  
Author(s):  
A. P. Halestrap ◽  
C. P. Connern ◽  
E. J. Griffiths ◽  
P. M. Kerr
Keyword(s):  
Cyclosporin A ◽  
Reperfusion Injury ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion

scholarly journals Different mechanisms of mitochondrial proton leak in ischaemia/reperfusion injury and preconditioning: implications for pathology and cardioprotection

2006 ◽  
Vol 395 (3) ◽  
pp. 611-618 ◽  
Author(s):  
Sergiy M. Nadtochiy ◽  
Andrew J. Tompkins ◽  
Paul S. Brookes
Keyword(s):  
Reperfusion Injury ◽  
Kinase Inhibitor ◽  
Adenine Nucleotide ◽  
Treatment Strategies ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Rat Hearts ◽  
Perfused Rat Hearts

The mechanisms of mitochondrial proton (H+) leak under various pathophysiological conditions are poorly understood. In the present study it was hypothesized that different mechanisms underlie H+ leak in cardiac IR (ischaemia/reperfusion) injury and IPC (ischaemic preconditioning). Potential H+ leak mechanisms examined were UCPs (uncoupling proteins), allosteric activation of the ANT (adenine nucleotide translocase) by AMP, or the PT (permeability transition) pore. Mitochondria isolated from perfused rat hearts that were subjected to IPC exhibited a greater H+ leak than did controls (202±27%, P<0.005), and this increased leakage was completely abolished by the UCP inhibitor, GDP, or the ANT inhibitor, CAT (carboxyattractyloside). Mitochondria from hearts subjected to IR injury exhibited a much greater amount of H+ leak than did controls (411±28%, P<0.001). The increased leakage after IR was weakly inhibited by GDP, but was inhibited, >50%, by carboxyattractyloside. In addition, it was inhibited by cardioprotective treatment strategies including pre-IR perfusion with the PT pore inhibitors cyclosporin A or sanglifehrin A, the adenylate kinase inhibitor, AP5A (diadenosine pentaphosphate), or IPC. Together these data suggest that the small increase in H+ leak in IPC is mediated by UCPs, while the large increase in H+ leak in IR is mediated by the ANT. Furthermore, under all conditions studied, in situ myocardial O2 efficiency was correlated with isolated mitochondrial H+ leak (r2=0.71). In conclusion, these data suggest that the modulation of H+ leak may have important implications for the outcome of IR injury.

scholarly journals Effects of Cardiovascular Risk Factors on Cardiac STAT3

2018 ◽  
Vol 19 (11) ◽  
pp. 3572 ◽  
Author(s):  
Márton Pipicz ◽  
Virág Demján ◽  
Márta Sárközy ◽  
Tamás Csont
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Reperfusion Injury ◽  
Cardiovascular Risk Factors ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Cardiac Cells ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Age Related

Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of cardiac cells, STAT3 promotes cardiac muscle differentiation, vascular element formation and extracellular matrix homeostasis. Overwhelming evidence suggests that STAT3 is beneficial for the heart, plays a role in the prevention of age-related and postpartum heart failure, protects the heart against cardiotoxic doxorubicin or ischaemia/reperfusion injury, and is involved in many cardioprotective strategies (e.g., ischaemic preconditioning, perconditioning, postconditioning, remote or pharmacological conditioning). Ischaemic heart disease is still the leading cause of death worldwide, and many cardiovascular risk factors contribute to the development of the disease. This review focuses on the effects of various cardiovascular risk factors (diabetes, aging, obesity, smoking, alcohol, depression, gender, comedications) on cardiac STAT3 under non-ischaemic baseline conditions, and in settings of ischaemia/reperfusion injury with or without cardioprotective strategies.

Mitochondrial protein kinase Cϵ (PKCϵ): emerging role in cardiac protection from ischaemic damage

2007 ◽  
Vol 35 (5) ◽  
pp. 1052-1054 ◽  
Author(s):  
G.R. Budas ◽  
D. Mochly-Rosen
Keyword(s):  
Protein Kinase ◽  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Permeability Transition ◽  
K Channel ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion

Mitochondria mediate diverse cellular functions including energy generation and ROS (reactive oxygen species) production and contribute to signal transduction. Mitochondria are also key regulators of cell viability and play a central role in necrotic and apoptotic cell death pathways induced by cardiac ischaemia/reperfusion injury. PKC (protein kinase C) ϵ plays a critical role in cardioprotective signalling pathways that protect the heart from ischaemia/reperfusion. Emerging evidence suggests that the cardioprotective target of PKCϵ resides at the mitochondria. Proposed mitochondrial targets of PKCϵ include mitoKATP (mitochondrial ATP-sensitive K+ channel), components of the MPTP (mitochondrial permeability transition pore) and components of the electron transport chain. This review highlights mitochondrial targets of PKCϵ and their possible role in cardioprotective signalling in the setting of ischaemia/reperfusion injury.

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

2012 ◽  
Vol 441 (3) ◽  
pp. 901-907 ◽  
Author(s):  
Henry Dube ◽  
David Selwood ◽  
Sylvanie Malouitre ◽  
Michela Capano ◽  
Michela I. Simone ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Binding Affinity ◽  
Specific Binding ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Fold Increase ◽  
Cyclophilin D ◽  
Ischaemia Reperfusion Injury ◽  
Rat Cardiomyocytes ◽  
Selective Targeting

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.

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