New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Mitochondrial Ion Channels and Cardioprotection

Nishida, Hitoshi; Sato, Toshiaki; Ogura, Takehiko; Nakaya, Haruaki

doi:10.1254/jphs.08r24fm

Cited by 24 publications

(17 citation statements)

References 58 publications

(36 reference statements)

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“…Likely, the mitoK ATP channel opening with subsequent ROS formation signalling is implicated in the CST-Post induced protection [13,15,31]. In fact ROS can activate a redundant pool of kinases involved in cardioprotection [7,13,18,35,41], including PKCs, thus eliciting a positive feed-back loop [47], which may provide a sort of cardioprotection memory (reverberant loop, Fig 4) [15].…”

Section: Cst-cardioprotective Effects Against Infarct Sizementioning

confidence: 99%

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Perrelli

Tullio

Angotti

et al. 2013

Pflugers Arch - Eur J Physiol

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Aims: Catestatin (CST) limits myocardial ischaemia/reperfusion (I/R) injury with unknown mechanisms. Clearly phosphoinositide-3-kinase (PI3K), protein-kinase-C (PKC) isoforms, including intra-mitochondrial PKCε, mitochondrial-K ATP (mitoK ATP ) channels and subsequent reactiveoxygen-species (ROS)-signalling play important roles in postconditioning cardioprotection, preventing mitochondrial permeability transition pore (mPTP) opening. Therefore, we studied the role of these extra-and intra-mitochondrial factors in CST-induced protection. Methods and Results: Isolated rat hearts and H9c2 cells underwent I/R and oxidative stress, respectively. In isolated hearts CST (75nM, CST-Post) given in early-reperfusion significantly reduced infarct-size, limited post-ischaemic contracture, and improved recovery of developed left ventricular pressure.PI3K inhibitor, LY-294002 (LY), large spectrum PKC inhibitor, Chelerythrine (CHE), specific PKCε inhibitor (εV1-2), mitoK ATP channel blocker, 5-Hydroxydecanoate (5HD) or ROS scavenger, 2-mercaptopropionylglycine (MPG) abolished the infarct-sparing effect of CST. Notably the CSTinduced contracture limitation was maintained during co-infusion of 5HD, MPG or εV1-2, but it was lost during co-infusion of LY or CHE. In H9c2 cells challenged with H 2 O 2 , mitochondrialdepolarization (an index of mPTP-opening studied with JC1-probe) was drastically limited by CST (75nM). Conclusions: Our results suggest that the protective signalling pathway activated by CST includes mitoK ATP channels, ROS-signalling and prevention of mPTP opening, with a central role for upstream PI3K/Akt and PKCs. In fact, all inhibitors completely abolished CST-infarct-sparing effect. Since CST-anti-contracture effect cannot be explained by intra-mitochondrial mechanisms (PKCε activation and mitoK ATP channel opening) or ROS-signalling, it is proposed that these downstream signals are part of a reverberant loop which re-activates upstream PKCs, which therefore play a pivotal role in CST-induced protection.

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Section: Cst-cardioprotective Effects Against Infarct Sizementioning

confidence: 99%

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Perrelli

Tullio

Angotti

et al. 2013

Pflugers Arch - Eur J Physiol

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“…In addition, when the electron-transport efficiency at complex I is suddenly inhibited or complex I activity is changed, this mechanism also generates O At the IMM, in addition to Ca 2 + channels/transporters, several K + channels, including mitoK ATP and mitochondrial Ca 2 + -activated K + channel (mitoK Ca ), are present. These channels indirectly modulate ROS generation in pathophysiological conditions such as ischemic/reperfusion (I/R) in the heart (36,124,127,128). Opening of mitoK ATP and mitoK Ca , either by cellular signal transduction or by extracellular stress such as I/R, depolarizes DJ m , which reduces the driving force for Ca 2 + influx, thereby attenuating mitochondrial Ca 2 + overload and excessive ROS generation.…”

Section: Fig 2 Mitochondrial Etc and Mitochondrial Ros Generationmentioning

confidence: 99%

Mitochondrial Ion Channels/Transporters as Sensors and Regulators of Cellular Redox Signaling

O‐Uchi

Ryu

Jhun

et al. 2014

Antioxidants & Redox Signaling

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Significance: Mitochondrial ion channels/transporters and the electron transport chain (ETC) serve as key sensors and regulators for cellular redox signaling, the production of reactive oxygen species (ROS) and nitrogen species (RNS) in mitochondria, and balancing cell survival and death. Although the functional and pharmacological characteristics of mitochondrial ion transport mechanisms have been extensively studied for several decades, the majority of the molecular identities that are responsible for these channels/transporters have remained a mystery until very recently. Recent Advances: Recent breakthrough studies uncovered the molecular identities of the diverse array of major mitochondrial ion channels/transporters, including the mitochondrial Ca 2+ uniporter pore, mitochondrial permeability transition pore, and mitochondrial ATP-sensitive K + channel. This new information enables us to form detailed molecular and functional characterizations of mitochondrial ion channels/transporters and their roles in mitochondrial redox signaling. Critical Issues: Redox-mediated post-translational modifications of mitochondrial ion channels/transporters and ETC serve as key mechanisms for the spatiotemporal control of mitochondrial ROS/RNS generation. Future Directions: Identification of detailed molecular mechanisms for redox-mediated regulation of mitochondrial ion channels will enable us to find novel therapeutic targets for many diseases that are associated with cellular redox signaling and mitochondrial ion channels/transporters. Antioxid. Redox Signal. 21, 987-1006.

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“…It is speculated that the depolarization by glibenclamide of the membrane of longitudinal smooth muscle cells may be due to the inhibition of ATP-sensitive K-channels distributed in the plasma membrane. The results also suggest that 5-HDA is selective to ATP-sensitive K-channels distributed in mitochondrial inner membrane, as in the case of cardiac muscle (Grover and Garlid, 2000;Sato et al, 2005;Nishida et al, 2009) . Difference in the effects of glibenclamide and 5-HDA on the duration of follower potentials suggests that the inhibition of the activity of mitochondrial ATP-sensitive K-channels is not a direct factor to determine the duration of pacemaker potentials, although detailed mechanism remains unclear.…”

Section: Discussionmentioning

confidence: 62%

“…In cardiac muscles, glibenclamide inhibits the activity of ATP-sensitive K-channels distributed in both plasma and mitochondrial membranes, while 5-HDA selectively inhibits these channels distributed in the mitochondrial membrane (Grover and Garlid, 2000;Pagliaro et al, 2002;Nakae et al, 2003;Ashcroft, 2005;Sato et al, 2005;Wang et al, 2008;Nishida et al, 2009). This seems to be also the case in gastric muscles, and spontaneous activity of gastric muscle is inhibited by both glibenclamide and 5-HDA (Fukuta et al, 2002;Kito and Suzuki, 2003a;Kito and Suzuki, 2003b).…”

Section: Discussionmentioning

confidence: 87%

Factors which determine the duration of follower potentials in longitudinal smooth muscle isolated from the guinea-pig stomach antrum

Shigemasa

Kito

Hashitani

et al. 2011

J. Smooth Muscle Res.

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In isolated longitudinal muscle tissues of the guinea-pig stomach antrum, recording electrical responses from smooth muscle cells revealed a periodical generation of follower potentials with variable durations. The I-D relationship, made by plotting the duration as a function of the interval before generating follower potential, was linear. Experiments were carried out to investigate the effects of chemicals which had been known to modulate the release of Ca 2+ from the internal stores (2-aminoethoxy-diphenyl-borate, cyclopiazonic acid, caffeine), inhibit mitochondrial metabolic activity (m-chlorophenyl hydrazone, 2-deoxy-Dglucose, potassium cyanide, rotenone), inhibit ATP-sensitive K-channels distributed in mitochondria (glibenclamide, 5-hydroxydecanoic acid) and inhibit the activity of proteinkinase C (chelerythrine), on the I-D relationship of follower potentials. The effects of depolarization on follower potentials were assessed by stimulating tissues with high potassium solution. Experiments were carried out mainly in the presence of nifedipine which minimized the movements of muscles with no modulation of follower potentials. Cycropiazonic acid and caffeine reduced the slope of I-D relationship, with associated reduction of the duration and frequency of follower potentials. 2-Aminoethoxydiphenyl borate reduced the duration and amplitude and increased the frequency of follower potentials, with depolarization of the membrane, and the effects were simulated by high potassium solution. m-Chlorophenyl hydrazone, potassium cyanide, 2-deoxy-D-glucose, rotenone, 5-hydroxydecanoic acid and glibenclamide reduced the slope of I-D relationship, with associated reduction of the frequency of follower potentials. Chelerythrine did not modulate the slope of I-D relationship, with reduced frequency of follower potentials. It seemed likely that the amount of Ca 2+ released from the internal stores and also mitochondrial function had causal relationship to the duration of pacemaker potentials, suggesting that internal Ca-stores and mitochondria are taking the central role for determining the duration of the pacemaker activity. Proteinkinase C did not seem to participate to the function of mitochondria and internal Ca 2+ stores.

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New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Mitochondrial Ion Channels and Cardioprotection

Cited by 24 publications

References 58 publications

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Catestatin reduces myocardial ischaemia/reperfusion injury: involvement of PI3K/Akt, PKCs, mitochondrial KATP channels and ROS signalling

Mitochondrial Ion Channels/Transporters as Sensors and Regulators of Cellular Redox Signaling

Factors which determine the duration of follower potentials in longitudinal smooth muscle isolated from the guinea-pig stomach antrum

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