scholarly journals Desflurane-induced post-conditioning against myocardial infarction is mediated by calcium-activated potassium channels: role of the mitochondrial permeability transition pore

2012 ◽  
Vol 108 (4) ◽  
pp. 594-601 ◽  
Author(s):  
J. Stumpner ◽  
M. Lange ◽  
A. Beck ◽  
T.M. Smul ◽  
C.A. Lotz ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Potassium Channels ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Permeability ◽  
Calcium Activated Potassium Channels

Abstract P234: S-nitrosylation of Cyclophilin D Attenuates Mitochondrial Permeability Transition Pore Opening: A Critical Role for Cysteine 203 Residue

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Tiffany T Nguyen ◽  
Mark V Stevens ◽  
Mark J Kohr ◽  
Charles Steenbergen ◽  
Michael N Sack ◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Protective Role ◽  
Nitric Oxide Donor ◽  
Cyclophilin D ◽  
Mitochondrial Permeability ◽  
Mptp Opening

S-nitrosylation (SNO), a reversible, redox-dependent post-translational modification, has emerged as an important mechanism for dynamic regulation of many proteins. Our previous studies have shown that protein S-nitrosylation (SNO) plays a protective role in myocardial ischemia/reperfusion (IR) injury. The primary mediator of cell death in I/R injury is activation of the mitochondrial permeability transition pore (mPTP). Using a proteomic approach, we have previously found that cyclophilin D (CypD), a critical mPTP regulator, can be SNO on cysteine 203 (C203). To investigate whether SNO of CypD might attenuate mPTP activation, we mutated cysteine 203 of CypD, to a serine residue (C203S) and determined its effects on mPTP opening by assessing H 2 O 2 -induced mPTP opening using the calcein AM-cobalt chloride quenching method. Treatment of CypD -/- mouse embryonic fibroblasts (MEFs) with H 2 O 2 resulted loss in an ≈50 % loss of mPTP opening as compared to WT MEFs (n=5, p<0.05), consistent with the protective role of CypD in mPTP activation. Addition of a nitric oxide donor, GSNO, to CypD -/- MEFs did not further reduce mPTP opening; however, WT MEFs treated GSNO attenuated mPTP opening by half. To elucidate the role of SNO of C203 on CypD, we infected CypD -/- MEFs with a C203S-CypD vector. C203S-CypD re-constituted MEFs were also resistant to mPTP opening in the presence or absence of GSNO. This suggests that C203 is required for mPTP activation. To determine whether in vivo expression of C203S-CypD would alter mPTP opening, we generated adenovirus vectors encoding WT CypD or mutated C203S-CypD and injected these viral particles into CypD -/- mice via tail-vein. Mitochondria isolated from livers of CypD -/- mice or mice expressing C203S-CypD were resistant to Ca 2+ -induced swelling as compared to WT CypD reconstituted mice. In summary, our results indicate that C203 of CypD is required for mPTP opening and for the first time shows that SNO of C203 on CypD acts to attenuate mPTP activation.

Sign in / Sign up

Export Citation Format

Share Document