Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning?

Hausenloy, Derek J.; Maddock, Helen; Baxter, GF; Yellon, Derek M.

doi:10.1016/s0008-6363(02)00455-8

Cited by 506 publications

(219 citation statements)

References 43 publications

Supporting

Mentioning

206

Contrasting

Unclassified

Order By: Relevance

“…During these measurements, MPTP opening was blocked by adding cyclosporine A [22], the proton channel of the ATP-synthase was blocked with oligomycin, and opening of ATP-dependent potassium (mitoK ATP ) channels were blocked by glibenclamide [62, 72]. However, even in the presence of these inhibitors and CBX a mitochondrial K + influx was still detected.…”

Section: Discussionmentioning

confidence: 99%

“…The kinetics of mitochondrial K + uptake were measured after a KCl pulse of 140 mmol at alternated excitations at 340/380 nm and emission at 500 nm by a fluorometer (Cary Eclipse spectrophometer; Varian, Mulgrave, Australia) in 2 ml isolation buffer at medium sensitivity. To measure the K + permeability for the Cx43 hemichannel only, during measurements, mitochondrial permeability transition pore (MPTP) opening was blocked by adding 1 µmol cyclosporine A (CsA; Sigma-Aldrich, Heidenheim, Germany) [22], the proton channel of the ATP-synthase was blocked with 1 µg/ml oligomycin (Sigma-Aldrich, Heidenheim, Germany), and opening of ATP-dependent potassium channels was blocked by 5 µmol glibenclamide (Sigma-Aldrich, Heidenheim, Germany) [62, 72]. The experiments were repeated without these inhibitors to investigate the influence of NO donors on the K + influx under more physiological conditions.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

S-nitrosation of mitochondrial connexin 43 regulates mitochondrial function

et al. 2014

View full text Add to dashboard Cite

S-nitrosation (SNO) of connexin 43 (Cx43)-formed channels modifies dye uptake in astrocytes and gap junctional communication in endothelial cells. Apart from forming channels at the plasma membrane of several cell types, Cx43 is also located at the inner membrane of myocardial subsarcolemmal mitochondria (SSM), but not in interfibrillar mitochondria (IFM). The absence or pharmacological blockade of mitochondrial Cx43 (mtCx43) reduces dye and potassium uptake. Lack of mtCx43 is associated with loss of endogenous cardioprotection by ischemic preconditioning (IPC), which is mediated by formation of reactive oxygen species (ROS). Whether or not mitochondrial Lucifer Yellow (LY), ion uptake, or ROS generation are affected by SNO of mtCx43 and whether or not cardioprotective interventions affect SNO of mtCx43 remains unknown. In SSM from rat hearts, application of NO donors (48 nmol to 1 mmol) increased LY uptake (0.5 mmol SNAP 38.4 ± 7.1 %, p < 0.05; 1 mmol GSNO 28.1 ± 7.4 %, p < 0.05) and the refilling rate of potassium (SNAP 227.9 ± 30.1 %, p < 0.05; GSNO 122.6 ± 28.1 %, p < 0.05). These effects were absent following blockade of Cx43 hemichannels by carbenoxolone as well as in IFM lacking Cx43. Unlike potassium, the sodium permeability was not affected by application of NO. Furthermore, mitochondrial ROS formation was increased following NO application compared to control SSM (0.5 mmol SNAP 22.9 ± 1.8 %, p < 0.05; 1 mmol GSNO 40.6 ± 7.1 %, p < 0.05), but decreased in NO treated IFM compared to control (0.5 mmol SNAP 14.4 ± 4 %, p < 0.05; 1 mmol GSNO 13.8 ± 4 %, p < 0.05). NO donor administration to isolated SSM increased SNO of mtCx43 by 109.2 ± 15.8 %. Nitrite application (48 nmol) to mice was also associated with elevated SNO of mtCx43 by 59.3 ± 18.2 % (p < 0.05). IPC by four cycles of 5 min of ischemia and 5 min of reperfusion increased SNO of mtCx43 by 41.6 ± 1.7 % (p < 0.05) when compared to control perfused rat hearts. These data suggest that SNO of mtCx43 increases mitochondrial permeability, especially for potassium and leads to increased ROS formation. The increased amount of SNO mtCx43 by IPC or nitrite administration may link NO and Cx43 in the signal transduction cascade of cardioprotective interventions.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-014-0433-x) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

S-nitrosation of mitochondrial connexin 43 regulates mitochondrial function

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The mitochondrial permeability transition pore (mPTP) is a critical determinant of cell death in I/R injury [20,21,22,23,24]. The disturbance of ion homeostasis resulting from ATP depletion following the opening of the mPTP can lead to necrotic and apoptotic cell death [25].…”

Section: Discussionmentioning

confidence: 99%

“…The disturbance of ion homeostasis resulting from ATP depletion following the opening of the mPTP can lead to necrotic and apoptotic cell death [25]. Prosurvival pathways involving PI3K-Akt and ERK1/2 have been shown to prevent cellular damage by converging on the mPTP and inhibiting its opening [1,21,22,23,24,25,26]. Moreover, UTI has been shown to protect mitochondrial function during I/R by directly inhibiting lysosomal enzymes and free radicals [8] or reducing Ca 2+ overload in injured cells [9].…”

Section: Discussionmentioning

confidence: 99%

Urinary Trypsin Inhibitors Afford Cardioprotective Effects through Activation of PI3K-Akt and ERK Signal Transduction and Inhibition of p38 MAPK and JNK

Kim

Yoo²,

Jeong³

et al. 2009

Cardiology

View full text Add to dashboard Cite

Background: We determined the effect of urinary trypsin inhibitors (UTI) in regional myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms involving the role of prosurvival kinases such as phosphatidylinositol-3-OH kinases (PI3K)-Akt and extracellular signal-regulated kinases (ERK 1/2) and apoptotic kinases such as p38 and JNK. Methods: The rats were anesthetized and subjected to an I/R insult consisting of 30-min left anterior descending coronary artery (LAD) occlusion followed by reperfusion. Infarct size was measured after 120 min of reperfusion. UTI was given alone or along with wortmannin (inhibitor of PI3K) or PD098059 (inhibitor of ERK1/2) before LAD occlusion. The phosphorylation of Akt, ERK1/2, p38 and JNK was determined by immunoblotting after 5 min of reperfusion. UTI was administered 10 min before LAD occlusion, and wortmannin and PD098059 were administered 20 min before LAD occlusion. Results: UTI significantly reduced the infarct size compared with the control. Wortmannin or PD098059 alone did not affect the infarct size, but they abolished the UTI-induced cardioprotective effect. UTI significantly reduced the phosphorylation of p38 and JNK, while it enhanced that of Akt and ERK1/2. Conclusions: UTI has a protective effect against regional myocardial I/R injury through activation of survival kinases PI3K-Akt and ERK1/2 and attenuation of p38 and JNK.

show abstract

“…Isoflurane was found to induce phosphorylation of GSK-3β, which was associated with mitochondrial protection and reduced IR injury due to attenuated mPTP opening (Juhaszova et al, 2004). Moreover, phosphorylation of GSK-3β was reported to increase binding of ANT with phosphorylated GSK-3β (Nishihara et al, 2007), which decreased binding of ANT with CyP-D and suppressed mPTP formation to ultimately confer cardioprotection (Hausenloy et al, 2002; Javadov et al, 2003). Future confirmation of the molecular identity of mPTP is indispensable to understanding VA-mediated mechanisms that would potentially retard mPTP opening and confer cardioprotection.…”

Section: Effects Of Va On Inner Mitochondrial Membrane Proteinsmentioning

confidence: 99%

Mitochondrial targets for volatile anesthetics against cardiac ischemia-reperfusion injury

et al. 2014

View full text Add to dashboard Cite

Mitochondria are critical modulators of cell function and are increasingly recognized as proximal sensors and effectors that ultimately determine the balance between cell survival and cell death. Volatile anesthetics (VA) are long known for their cardioprotective effects, as demonstrated by improved mitochondrial and cellular functions, and by reduced necrotic and apoptotic cell death during cardiac ischemia and reperfusion (IR) injury. The molecular mechanisms by which VA impart cardioprotection are still poorly understood. Because of the emerging role of mitochondria as therapeutic targets in diseases, including ischemic heart disease, it is important to know if VA-induced cytoprotective mechanisms are mediated at the mitochondrial level. In recent years, considerable evidence points to direct effects of VA on mitochondrial channel/transporter protein functions and electron transport chain (ETC) complexes as potential targets in mediating cardioprotection. This review furnishes an integrated overview of targets that VA impart on mitochondrial channels/transporters and ETC proteins that could provide a basis for cation regulation and homeostasis, mitochondrial bioenergetics, and reactive oxygen species (ROS) emission in redox signaling for cardiac cell protection during IR injury.

show abstract

Inhibiting mitochondrial permeability transition pore opening: a new paradigm for myocardial preconditioning?

Abstract: One interpretation of these data is that IPC and mitochondrial K(ATP) channel activation may protect the myocardium by inhibiting MPTP opening at reperfusion.

Cited by 506 publications

References 43 publications

S-nitrosation of mitochondrial connexin 43 regulates mitochondrial function

S-nitrosation of mitochondrial connexin 43 regulates mitochondrial function

Urinary Trypsin Inhibitors Afford Cardioprotective Effects through Activation of PI3K-Akt and ERK Signal Transduction and Inhibition of p38 MAPK and JNK

Mitochondrial targets for volatile anesthetics against cardiac ischemia-reperfusion injury

Contact Info

Product

Resources

About