Mitochondrial KATPChannel as an End Effector of Cardioprotection During Late Preconditioning: Triggering Role of Nitric Oxide

Wang, Yigang; Kudo, Mitsuhiro; Xu, Meifeng; Ayub, Ahmar; Ashraf, Muhammad

doi:10.1006/jmcc.2001.1468

Cited by 92 publications

(72 citation statements)

References 34 publications

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“…Hence, consistently, in TcdB-exposed epithelial cells, treatment with the mK ATP channel opener diazoxide resulted in the maintenance of mitochondrial ionic homeostasis and mitochondrial membrane potential and in apoptosis hindering. This could parallel the results previously obtained in other experimental systems, such as ischemic brain injury protection (44) or cardioprotection (38). Intriguingly, a cardiotoxic effect of TcdB, both in primary cardiomyocytes and in zebrafish embryo, has very recently been reported by Hamm et al (45).…”

Section: Discussionsupporting

confidence: 86%

“…As concerns the mK ATP channels, their involvement in TcdB activity was principally proved by the observation that their pharmacological activation by specific openers, such as diazoxide or pinacidil, significantly prevented either mitochondrial hyperpolarization or apoptosis, whereas the addition of the mK ATP channel inhibitor 5HD restored the sensitivity to TcdBinduced effects. So far, the mK ATP channels have been identified in the inner mitochondrial membrane of the liver (36), cardiac (37,38), neural (39), and lymphoblastoid cells (40). Their opening was demonstrated to lead to an enhanced resistance to injuries caused by different stimulations, including those of apoptotic inducers (40 -43).…”

Section: Discussionmentioning

confidence: 99%

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Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Matarrese

Falzano

Fabbri

et al. 2007

Journal of Biological Chemistry

107

109

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Targeting to mitochondria is emerging as a common strategy that bacteria utilize to interact with these central executioners of apoptosis. Several lines of evidence have in fact indicated mitochondria as specific targets for bacterial protein toxins, regarded as the principal virulence factors of pathogenic bacteria. This work shows, for the first time, the ability of the Clostridium difficile toxin B (TcdB), a glucosyltransferase that inhibits the Rho GTPases, to impact mitochondria. In living cells, TcdB provokes an early hyperpolarization of mitochondria that follows a calcium-associated signaling pathway and precedes the final execution step of apoptosis (i.e. mitochondria depolarization). Importantly, in isolated mitochondria, the toxin can induce a calcium-dependent mitochondrial swelling, accompanied by the release of the proapoptogenic factor cytochrome c. This is consistent with a mitochondrial targeting that does not require the Rho-inhibiting activity of the toxin. Of interest, the mitochondrial ATP-sensitive potassium channels are also involved in the apoptotic response to TcdB and appear to be crucial for the cell death execution phase, as demonstrated by using specific modulators of these channels. To our knowledge, the involvement of these mitochondrial channels in the ability of a bacterial toxin to control cell fate is a hitherto unreported finding.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Matarrese

Falzano

Fabbri

et al. 2007

Journal of Biological Chemistry

107

109

View full text Add to dashboard Cite

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“…41 A water-filled balloon was inserted into the left ventricle and adjusted to a left ventricular end-diastolic pressure (LVEDP) of 5 to 8 mm Hg. The distal end of the catheter was connected to a Digi-Med Heart Performance Analyzer-via a pressure transducer (Case).…”

Section: Langendorff Heart Preparation and Measurements Of Cardiac Fumentioning

confidence: 99%

“…41 ATP was extracted from 20 to 80 mg of freeze-dried left ventricle collected at the end of ischemia or after termination of the experiment and analyzed by spectrophotometry. 41 …”

Section: Measurement Of Lactate Dehydrogenase and Atpmentioning

confidence: 99%

Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

Wang

Meyer

Ashraf

et al. 2003

Circulation Research

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Abstract-Pharmacological studies indicate that Naϩ -H ϩ exchanger isoform 1 (NHE1) plays a central role in myocardial ischemia-reperfusion injury; however, confirmation by alternative methods is lacking. To address this issue, we examined the role of NHE1 in ischemia-reperfusion injury using gene-targeted NHE1-null mutant (Nhe1 Ϫ/Ϫ ) mice. Nhe1Ϫ/Ϫ and wild-type hearts were perfused in a Langendorff apparatus in both the absence and presence of the NHE1 inhibitor eniporide, subjected to 40 minutes of ischemia and 30 minutes of reperfusion, and the effects of genetic ablation or inhibition of NHE1 on hemodynamic, biochemical, and pathological changes were assessed. In the absence of eniporide, left ventricular developed pressure, end-diastolic pressure, and coronary flow were significantly less impaired in Nhe1 Ϫ/Ϫ hearts relative to wild-type hearts, and release of lactate dehydrogenase, morphological damage, and ATP depletion were also significantly less. In the presence of eniporide, however, wild-type hearts were significantly protected and there were no significant differences between the two genotypes with respect to cardiac performance, lactate dehydrogenase release, or morphological damage. Furthermore, the presence or absence of eniporide had no apparent effect on the degree of cardioprotection observed in Nhe1 Ϫ/Ϫ hearts. These data demonstrate that genetic ablation of NHE1 protects the heart against ischemia-reperfusion injury. In addition to providing direct evidence that confirms previous pharmacological studies indicating a role for NHE1 in ischemia-reperfusion injury, these results suggest that the long-term absence of NHE1 does not elicit major compensatory changes that might negate the cardioprotective effects of blocking its activity over the short-term.

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“…However, it was not known whether this protection involved a drug-initiated mechanism similar to that seen with IPC. The IPC response in tissues, normally initiated by hypoxic conditions, can be triggered by ROS and/or nitric oxide (NO), which activate PKG and mitochondrial PKCe, resulting in the activation of the mitochondrial ATP-sensitive K + [mK(ATP)] channel (19). This blocks the formation of the mitochondrial permeability transition pore (MPTP) and prevents the cell from initiating an apoptotic response (20).…”

Section: Sulindac Protection Of Rpe Cells Involves Both Mitochondrialmentioning

confidence: 99%

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

Sur

Kesaraju

Prentice

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The retinal pigmented epithelial (RPE) layer is one of the major ocular tissues affected by oxidative stress and is known to play an important role in the etiology of age-related macular degeneration (AMD), the major cause of blinding in the elderly. In the present study, sulindac, a nonsteroidal antiinflammatory drug (NSAID), was tested for protection against oxidative stressinduced damage in an established RPE cell line . Besides its established antiinflammatory activity, sulindac has previously been shown to protect cardiac tissue against ischemia/reperfusion damage, although the exact mechanism was not elucidated. As shown here, sulindac can also protect RPE cells from chemical oxidative damage or UV light by initiating a protective mechanism similar to what is observed in ischemic preconditioning (IPC) response. The mechanism of protection appears to be triggered by reactive oxygen species (ROS) and involves known IPC signaling components such as PKG and PKC epsilon in addition to the mitochondrial ATP-sensitive K + channel. Sulindac induced iNOS and Hsp70, late-phase IPC markers in the RPE cells. A unique feature of the sulindac protective response is that it involves activation of the peroxisome proliferator-activated receptor alpha (PPAR-α). We have also used low-passage human fetal RPE and polarized primary fetal RPE cells to validate the basic observation that sulindac can protect retinal cells against oxidative stress. These findings indicate a mechanism for preventing oxidative stress in RPE cells and suggest that sulindac could be used therapeutically for slowing the progression of AMD.preconditioning | oxidative stress | sulindac | retinal pigmented epithelial cells | age-related macular degeneration O xidative damage, resulting from excess production of reactive oxygen species (ROS), has been implicated in the progression of key ocular disorders such as cataracts, glaucoma, and age-related macular degeneration (AMD). Death of retinal pigmented epithelial (RPE) cells has been shown to be an important contributor to AMD pathophysiology. RPE cells are known to be highly metabolically active, and there is strong evidence that the RPE cells are sensitive to oxidative stress (1). It has been reported that the pathophysiology of AMD is due to cumulative oxidative damage to RPE cells resulting from an imbalance between the generation of ROS and the ability of these cells to destroy and/or protect against ROS damage to macromolecules (2, 3). Hence, strategies for protecting RPE cells against oxidative damage may be particularly important in maintaining retinal function and preventing the development or progression of AMD.Sulindac was one of the first nonsteroidal antiinflammatory drugs (NSAIDs) used to treat inflammation. It is a prodrug, composed of R and S epimers, whose NSAID activity is dependent on the reduction of the epimers to sulindac sulfide, the active cyclooxygenase (COX) inhibitor (4). This reduction is catalyzed by two members of the methionine sulfoxide reductase (Msr) family, MsrA and MsrB,...

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Mitochondrial KATPChannel as an End Effector of Cardioprotection During Late Preconditioning: Triggering Role of Nitric Oxide

Cited by 92 publications

References 34 publications

Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

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Mitochondrial KATPChannel as an End Effector of Cardioprotection During Late Preconditioning: Triggering Role of Nitric Oxide

Cited by 92 publications

References 34 publications

Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria

Mice With a Null Mutation in the NHE1 Na + -H + Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

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Resources

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Mice With a Null Mutation in the NHE1 Na ⁺ -H ⁺ Exchanger Are Resistant to Cardiac Ischemia-Reperfusion Injury