Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

McLeod, Christopher J.; Jeyabalan, Anandhi P.; Minners, Jan; Clevenger, Randall R.; Hoyt, Robert F.; Sack, Michael N.

doi:10.1161/01.cir.0000136997.53612.6c

Cited by 59 publications

(42 citation statements)

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“…Accumulating evidences proved that the induction of PGC-1α increased the mitochondria tolerance to hypoxia-reoxygenation injury. 26,27) Several studies have shown that low PGC-1α expression is probably involved in cell apoptosis. 28,29) Our data showed that DT-010 significantly reduced apoptotic cells and markedly increased the expression of PGC-1α, Nrf2 and Tfam, indicating that the up-regulation of PGC-1α could protect cardiomyocytes from t-BHP induced oxidative injury.…”

Section: Discussionmentioning

confidence: 99%

A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway

Zhang¹,

Hu²,

Luo³

et al. 2017

Biological & Pharmaceutical Bulletin

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In this study, we investigated the cardioprotective mechanisms of action of DT-010, a novel danshensutetramethylpyrazine conjugate. DT-010 significantly preserved cell viability and suppressed cell apoptosis in H9c2 cells injured by tert-butylhydroperoxide (t-BHP), iodoacetic acid (IAA) and hypoxia-reoxygenation. In addition, DT-010 pre-treatment reduced the intracellular level of free radicals including superoxide anion (·O 2 ), hydroxyl radical (·OH) and peroxynitrite anion (ONOO ) after t-BHP exposure. Moreover, DT-010 up-regulated the protein expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) as well as mitochondrial transcription factor A (Tfam) and heme oxygenase-1 (HO-1) in H9c2 cells. DT-010 also triggered Nrf2 nuclear translocation. In a rat myocardial ischemia-reperfusion model, DT-010 significantly alleviated myocardial infarction. The results indicated that DT-010 may be a promising candidate for the treatment of cardiovascular diseases, particularly myocardial ischemia and reperfusion injury.Key words Danshensu derivative; oxidative stress; apoptosis; myocardial ischemia reperfusion injury; peroxisome proliferator-activated receptor gamma coactivator 1 alpha/nuclear factor-E2-related factor 2/heme oxygenase-1 (PGC-1α/Nrf2/HO-1) pathway Myocardial ischemia is a primary cause of sudden death worldwide. Myocardial ischemia results from a decreased blood flow to the heart, preventing the heart from receiving adequate supply of energy. The reduced blood flow is usually caused by a partial or complete blockade of the arteries. Traditional treatments focus on restoring blood supply, such as by pass-graft surgery, dilation of coronary artery and coronary thrombolysis, and etc. 1) Although restoration of blood flow to the ischemic heart tissues is important, it is not adequate because myocardial ischemic damage is progressively developed following reperfusion due to an over-production of a large number of biospecies. 2,3) Compelling evidence demonstrated that free radicals generated during ischemia and reperfusion play pivotal roles in myocardial apoptosis. Free radical scavengers can effectively inhibit myocardial apoptosis. The previous studies have demonstrated that agents that combine anti-thrombolytic and anti-oxidative activities showed promising therapeutic efficacy in the treatment of myocardial ischemia. 4,5) In China, many traditional herbs have been used to prevent and treat myocardial ischemia. Among them are Salvia miltiorrhiza (Danshen) and Ligusticum wallichii (Chuanxiong). As the major active ingredients, (3-(3,4-dihydroxyphenyl) lactic acid) (Danshensu, DSS, Fig. 1) isolated from Danshen and tetramethylpyrazine (TMP, Fig. 1) isolated from Chuanxiong have a variety of biological activities. They lyse blood clot, dilate coronary arteries, inhibit platelet aggregation, scavenge free radicals, improve microcirculation and have anti-inflammatory properties. 6,7) Both of them are widely used in clinic for treatm...

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Section: Discussionmentioning

confidence: 99%

A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway

Zhang¹,

Hu²,

Luo³

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Once asystole was achieved, the heart was immediately cooled to 4°C. The heart was then explanted and placed on a Langendorff perfusion rig 19. The ex vivo functioning of the hearts was maintained using a large animal Langendorff apparatus (Radnoti, Monrovia, CA).…”

Section: Methodsmentioning

confidence: 99%

Elimination of Purkinje Fibers by Electroporation Reduces Ventricular Fibrillation Vulnerability

Livia

Sugrue

Witt

et al. 2018

JAHA

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BackgroundThe Purkinje network appears to play a pivotal role in the triggering as well as maintenance of ventricular fibrillation. Irreversible electroporation (IRE) using direct current has shown promise as a nonthermal ablation modality in the heart, but its ability to target and ablate the Purkinje tissue is undefined. Our aim was to investigate the potential for selective ablation of Purkinje/fascicular fibers using IRE.Methods and ResultsIn an ex vivo Langendorff model of canine heart (n=8), direct current was delivered in a unipolar manner at various dosages from 750 to 2500 V, in 10 pulses with a 90‐μs duration at a frequency of 1 Hz. The window of ventricular fibrillation vulnerability was assessed before and after delivery of electroporation energy using a shock on T‐wave method. IRE consistently eradicated all Purkinje potentials at voltages between 750 and 2500 V (minimum field strength of 250–833 V/cm). The ventricular electrogram amplitude was only minimally reduced by ablation: 0.6±2.3 mV (P=0.03). In 4 hearts after IRE delivery, ventricular fibrillation could not be reinduced. At baseline, the lower limit of vulnerability to ventricular fibrillation was 1.8±0.4 J, and the upper limit of vulnerability was 19.5±3.0 J. The window of vulnerability was 17.8±2.9 J. Delivery of electroporation energy significantly reduced the window of vulnerability to 5.7±2.9 J (P=0.0003), with a postablation lower limit of vulnerability=7.3±2.63 J, and the upper limit of vulnerability=18.8±5.2 J.ConclusionsOur study highlights that Purkinje tissue can be ablated with IRE without any evidence of underlying myocardial damage.

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“…Animal Experiments-The ischemic preconditioning trigger was achieved by conferring transient regional ischemia to the left coronary artery of Wistar rats as described previously (3). Here, the heart was subjected to five episodes of 3 min of ischemia coupled to 5 min of reperfusion.…”

Section: Methodsmentioning

confidence: 99%

“…The mechanistic links between the molecular adaptations of the mitochondrion and the preconditioning cell survival program require further characterization. Further credence to the importance of mitochondrial adaptation to preconditioning-induced cell survival has been shown by improved mitochondrial respiratory and bioenergetic recovery following anoxia and reoxygenation in mitochondria extracted from ischemic, genomic, and pharmacologic preconditioned hearts (3)(4)(5). In addition, preconditioned mitochondria generate less reactive oxygen species (ROS) 3 at reoxygenation than do nonpreconditioned mitochondria (5-7).…”

mentioning

confidence: 99%

“…Further credence to the importance of mitochondrial adaptation to preconditioning-induced cell survival has been shown by improved mitochondrial respiratory and bioenergetic recovery following anoxia and reoxygenation in mitochondria extracted from ischemic, genomic, and pharmacologic preconditioned hearts (3)(4)(5). In addition, preconditioned mitochondria generate less reactive oxygen species (ROS) 3 at reoxygenation than do nonpreconditioned mitochondria (5-7). The broad molecular regulatory programs underpinning mitochondrial adaptations in preconditioning is further underscored by additional modulations in nuclear-encoded proteins modulating mitochondrial function during preconditioning (8,9).…”

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confidence: 99%

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Uncoupling Proteins 2 and 3 Function in Concert to Augment Tolerance to Cardiac Ischemia

McLeod

Aziz

Hoyt

et al. 2005

Journal of Biological Chemistry

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139

108

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Transient cardiac ischemia activates cell survival signaling, conferring subsequent ischemia tolerance to the heart. This biological phenomenon, termed ischemic preconditioning, results in improved clinical outcome and attenuated infarct size following myocardial infarction. To explore genomic modifications underpinning this ischemia tolerance, we delineated the regulation and function of the cardiac enriched mitochondrial uncoupling proteins 2 and 3 during delayed ischemic preconditioning in the rat. Cardiac transcripts of genes encoding uncoupling proteins 2 and 3 are upregulated in parallel with infarct size reduction in preconditioned hearts. Mitochondria isolated from preconditioned hearts exhibit an augmented inducible proton leak. In parallel, following anoxiareoxygenation these mitochondria generate less hydrogen peroxide compared with non-preconditioned mitochondria. Preconditioning in rat cardiac derived myoblasts is abolished following uncoupling protein-2 depletion by RNA-interference. RNAi of uncoupling protein-3 partially attenuates the capacity to precondition these cells. Functional characterization of anoxia and reoxygenation tolerance following uncoupling protein 2 or 3 and combined 2 and 3 RNAi shows the largest reduction in viability follows depletion of both homologues. Uncoupling protein-2 depletion alone significantly attenuates anoxia-reoxygenation tolerance but uncoupling protein-3 depletion does not reduce anoxia tolerance. In parallel combined uncoupling protein depletion and isolated uncoupling protein-2 depletion augments ROS production in viable cardiomyocytes following anoxia-reoxygenation. Concurrent antioxidant administration ameliorates the uncoupling protein-depleted anoxia-susceptible phenotype. In conclusion, mitochondrial uncoupling proteins are necessary components of ischemia tolerance and function as components of the cellular antioxidant defense program. In the cytoprotective hierarchy, uncoupling protein-2 appears to play a greater role than uncoupling protein-3 in modulating ischemia/anoxia tolerance in heart-derived cells.The cell survival program, termed ischemic preconditioning, evoked by transient nonlethal tissue ischemia, is evolutionarily conserved and is evident across multiple organs/tissues. The signal transduction networks engendering this phenomenon are well described (1); however, functional cellular modifications conferring ischemia tolerance are less tangible. Interestingly, the invariable metabolic signature of preconditioned tissue is enhanced capacity to restore mitochondrial function and ATP production following an ischemic insult (2). The mechanistic links between the molecular adaptations of the mitochondrion and the preconditioning cell survival program require further characterization. Further credence to the importance of mitochondrial adaptation to preconditioning-induced cell survival has been shown by improved mitochondrial respiratory and bioenergetic recovery following anoxia and reoxygenation in mitochondria extracted from ischemic, genomi...

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Delayed Ischemic Preconditioning Activates Nuclear-Encoded Electron-Transfer-Chain Gene Expression in Parallel With Enhanced Postanoxic Mitochondrial Respiratory Recovery

Cited by 59 publications

References 36 publications

A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway

A Novel Danshensu-Tetramethylpyrazine Conjugate DT-010 Provides Cardioprotection through the PGC-1α/Nrf2/HO-1 Pathway

Elimination of Purkinje Fibers by Electroporation Reduces Ventricular Fibrillation Vulnerability

Uncoupling Proteins 2 and 3 Function in Concert to Augment Tolerance to Cardiac Ischemia

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