Abstract
Hypoxia-reoxygenation injury is a commonly used in vitro model of ischemia, which is useful to study the recovery processes following the hypoxic period. Hypoxia can be rapidly induced in vitro by replacing the culture atmosphere with hypoxic or anoxic gas mixture. Cellular injury mostly occurs as a result of energetic failure in this model: the lack of oxygen blocks the mitochondrial respiration and anaerobic metabolism becomes the major source of high-energy molecules in the cells. In the absence of glucose, glycolysis and pentose phosphate pathway fail to suffice the cellular energy prerequisite and longer periods of oxygen-glucose deprivation (OGD) can completely deplete the cellular NAD+ and ATP pools. The lack of NAD+ results in severe metabolic suppression and predisposes the cells to other injury types. This includes oxidant-induced damage, since oxidative stress activates poly(ADP-ribose) polymerase (PARP) that further depletes the cellular NAD+ pool and leads to excessive cell death. The impaired mitochondrial respiration also leads to an increase in the mitochondrial membrane potential and augments the mitochondrial superoxide generation leading to oxidative stress. The above processes ultimately lead to necrotic cell death, but in certain cell types, mitochondrial damage can also trigger apoptosis.
Keywords
- hypoxia-reoxygenation injury
- poly(ADP-ribose) polymerase
- energetic failure
- mitochondrial dysfunction
- oxidative stress
1. Introduction
This chapter gives an overview of the hypoxia-reoxygenation model, provides guidance to perform hypoxia-reoxygenation or oxygen-glucose deprivation (OGD) experiments and discusses the mechanism of cellular damage in this model.
2. Hypoxia-reoxygenation induction
The hypoxia/OGD models are simple experimental models that do not require expensive laboratory instruments. Regular cell culture plasticware can be placed in a gas-tight chamber and the culture atmosphere replaced with oxygen-free gas mixture using an inexpensive flow meter. In addition, OGD can be induced by replacement of the culture medium with glucose-free medium. The reoxygenation period is initiated by glucose supplementation and by returning the culture vessels to regular atmosphere. The severity of the injury can be adjusted to specific needs by varying the length of the hypoxic/OGD period. Therapeutic interventions may be delivered prior to hypoxia induction or immediately following the reoxygenation modelling preventive or reperfusion therapies.
In most hypoxia experiments, above the hypoxic and OGD groups it is essential to use normoxia controls with normal glucose concentration or to expose normoxic controls to glucose deprivation (GD). Since the normoxic and hypoxic cells must be physically separated during the hypoxic period, identical cell plates must be prepared for the hypoxia and simultaneous normoxia exposures. Culture medium is replaced with fresh medium either containing glucose or without glucose prior to the induction of hypoxia. Serum deprivation may be necessary for complete removal of glucose in OGD injury. To induce hypoxia, the culture plates are placed in gas-tight incubation chambers (Billups-Rothenberg Inc., Del Mar, CA) and the chamber is flushed with oxygen-free gas mixture at 25–30 L/min flow rate for 5–10 min to completely remove oxygen [1–5, 7, 10]. Hypoxia is maintained by clamping and incubating the chambers at 37°C for the requested period. The composition of the gas mixture may vary depending on the bicarbonate content of the culture medium and the required level of acidity change (pH level), since hypercapnia can mimic the rapid development of acidic pH of ischemic tissues [11]. The CO2 content is typically between 5 and 20% with 80–95% N2. This procedure removes oxygen from the atmosphere but dissolved oxygen remains in all fluids in the chamber including the culture medium and additionally in water used for humidification, thus complete anoxia is reached with a delay, following depletion of the remaining oxygen. Following the hypoxic exposure, restoration of the normal culture conditions is achieved by supplementing the culture medium with glucose and foetal bovine serum (FBS) and by reoxygenating the culture vessels in regular culture atmosphere. In most cells, the cellular ATP level is recovered during a recovery period of 16–24 hours that might be the period of interest in most experiments.
Drug treatments may be administered before the hypoxia induction to test preventive effects or following the hypoxic period to test the therapeutic potential in ischemic diseases [1–3]. For gene silencing small interfering RNAs may be added 48 hours prior to the hypoxia exposure to effectively reduce RNA and protein levels of the gene of interest at the time of the hypoxia experiment [4, 5]. Unfortunately, gene silencing cannot be selectively used to study the hypoxic or the reoxygenation phase. Pharmacological treatments using small compounds allow specific post-hypoxic treatments that permit the specific study of the recovery phase.
3. Mechanism of cellular damage in hypoxia-reoxygenation injury
3.1. Cellular energy depletion
Hypoxia and glucose deprivation cause energy depletion in the cells and may be directly responsible for the viability reduction caused by the injury. Since the lack of oxygen blocks aerobic metabolism, which is responsible for the larger part of ATP production in the cells, the cells need to use other pathways to produce sufficient ATP for survival. Most cells can adapt to low oxygen conditions in cell culture, producing ATP solely by anaerobic metabolism if adequate glucose supply is present. However, the anaerobic pathways, glycolysis and pentose phosphate pathway need to use high amounts of glucose to produce comparable output. Glycolysis produces only two ATP molecules, but oxidative phosphorylation is capable to produce ~30 ATPs per glucose molecule oxidized [12]. The typical mitochondrial ATP production is lower than the theoretical maximum, since up to 20% of the basal metabolic rate may be used to drive the proton leak [13], but it is still more than 10 times higher than the anaerobic ATP production. The compensatory increase in anaerobic metabolism would be stopped by the limited availability of NAD+, since protons are transferred to NAD+ by glyceraldehyde phosphate dehydrogenase to produce NADH during glycolysis, if lactate dehydrogenase (LDH) did not recycle NAD+. This step helps maintain the higher anaerobic metabolic rate, but at the expense of metabolic acidosis (lactic acidosis).
However, in the absence of glucose, the ATP production will drop rapidly as the cellular energy storage is depleted and cell death will be induced. Most cells can survive in culture if the cellular ATP concentration will be reduced by less than 75–80% the normal ATP level [1–3, 5]. Following an OGD injury that does not reduce the cellular ATP concentration below 20% of the initial baseline value full recovery is expectable if optimal culture conditions are provided. Since the cells try to maintain normal ATP level and use all resources that can be utilized for energy production during the OGD phase, the recovery process is time-consuming: all precursor molecules need to be resynthesized in the cells. A more robust injury that decreases the cellular ATP concentration below 20% will initiate severe viability loss in the cell population [2] (Figure 1).
The cellular energy production remains impaired following an OGD injury: the cellular ATP production is slow even if the energy sources are provided in liberal amounts. The loss of all high-energy molecules is responsible for the diminished ATP synthesis following OGD. Not only ATP, but also adenosine diphosphate (ADP) and NAD+ are greatly reduced in the cells to minimize the ATP loss that will sustain the metabolic suppression [5]. ATP is the central coenzyme in the cells that functions as universal energy currency to transfer chemical energy. ATP molecules are generated in large quantities by constant recycling of ADP to ATP; the daily estimated ATP synthesis is around 1000 g/kg bodyweight [14]. Organic compounds are catabolized via a series of redox reactions in the cells and ultimately generate carbon dioxide and water. During these reactions, energy is collected via transferring electrons from organic donors to the acceptor molecule NAD+ and reducing it to NADH. Energy is retrieved from NADH in the mitochondria as the electrons are gradually transferred to oxygen through the electron transport chain and ATP is produced in the coupled oxidative phosphorylation reaction. Thus, the energy stored by NAD+ molecules is interconvertible to ATP molecules and the lack of NAD+ can severely limit the ATP generation.
NAD+ biosynthesis occurs either via the
The lack of NAD+ affects both mitochondrial respiration and anaerobic metabolism following the OGD injury [5]. Severe metabolic suppression is detectable following the OGD injury if the resynthesis of NAD+ is prevented by NamPRT inhibition: the mitochondrial oxygen consumption of the cells is severely reduced in the cells (Figure 3). The respiratory capacity of the cells is suppressed following OGD and while normal cells typically use no more than ~50–60% of their respiratory capacity under baseline conditions, the cells use their full respiratory capacity following hypoxia of OGD injury. While the basal anaerobic metabolism is less affected by the lack of NAD+ the anaerobic compensation is reduced by 70%, which makes the cells extremely sensitive to other injuries that require excess energy. At this stage, NAD+ is functionally shared between the mitochondrial and cytoplasmic pools, as the blockage of mitochondrial NAD+ recycling by inhibition of ATP synthase immediately draws a halt to anaerobic metabolism. This phenomenon can help explain the vulnerability of the cells: any injury that causes mitochondrial impairment can simultaneously block the anaerobic metabolism in the cells.
3.2. Oxidative stress during reoxygenation
Oxidative stress is an important contributor to cellular damage in hypoxia- or OGD-reoxygenation injury. While it is recognized as the major cause of cellular damage in ischemia-reperfusion injury
Superoxide is produced by the mitochondrial electron transport chain itself, most importantly at complex III: a low percentage of electrons from quinone molecules are transferred to oxygen instead of complex III even in healthy mitochondria [30–34]. The amount of ROS generation is relatively low, approximately 0.2–2% of the oxygen consumed by the mitochondria is reduced to superoxide [28]. However, this process would leave behind excess protons in the intermembrane space and increase the mitochondrial membrane potential, if mitochondria did not possess a safety mechanism against it. Uncoupling proteins and especially UCP2 are responsible for protecting against hyperpolarization. The elevated mitochondrial membrane potential directly increases the mitochondrial superoxide generation [35, 36]. This action is reversible: if the mitochondrial membrane potential is normalized, the superoxide generation will decrease to normal levels [27, 34, 37]. However, the action of UCP2 and UCP3 is regulated by reactive oxygen species (ROS) generation as their activity is affected by glutathionylation: increase in ROS production prompts the deglutathionylation and activation of proton conductivity via UCP2 and UCP3, while at low ROS levels the uncoupling proteins are glutathionylated that effectively deactivates the proton conductance process [28, 38]. During hypoxia or OGD, the absence of oxygen completely deactivates UCPs in the cell and it excludes the compensation for the hyperpolarization in the beginning of the reoxygenation phase. While an increase is detectable in the mitochondrial membrane potential, the amount of superoxide generation hardly exceeds the normal levels immediately following hypoxia or OGD due to the suppressed mitochondrial activity [5], but increased ROS production can be detected in the cells even after full recovery of the cellular ATP and NAD+ contents [5] (Figure 4).
Oxidative stress damages the DNA and RNA molecules causing modified bases and strand breaks and also induces oxidative protein damage. To minimize further dysfunction caused by impaired molecules, repair processes are promptly activated in the cells and PARP-1 is the key enzyme that orchestrates this process. The activation of PARP-1 is an easily detectable sign of oxidative stress in the cells and tissues [39–41].
3.3. The function of PARP-1 and its role in oxidative stress-induced cell death
PARP-1 is the major isoform of poly(ADP-ribose) polymerases in the cells that mainly resides in the nucleus. It detects DNA strand breaks and plays a role in base excision repair by adding multiple ADP-ribose units to the DNA associated histone proteins using NAD+ as a substrate. It promotes DNA repair by recruiting components of the repair machinery and also by providing sequestered energy source for the repair in the form of ADP-ribose. Poly(ADP-ribose) (PAR) induces conformation changes in the DNA due to its negative charge, which may serve as a surface for interaction in DNA repair. The removal of PAR is catalyzed by poly(ADP-ribose) glycohydrolase (PARG), an enzyme that is mainly localized to the cytoplasm and needs to translocate to the nucleus to counteract PARP.
While the far-reaching activity of PARP-1 in DNA repair suggests that it is essential for DNA integrity and cell survival, PARP-1 knockout mice are viable and do not exhibit high susceptibility for spontaneous tumour development [42]. There is no human ‘PARP-1 deficiency syndrome’. Single nucleotide polymorphisms of the PARP gene have been identified, but only few studies found association with functional changes and increased risk of cancer, nephritis or arthritis [43–46]. DNA repair processes possibly rely on redundant actions of many other components or PARP-1 is substituted by other PARP isoforms [47, 48]. On the other hand, the principal role of PARP-1 is indisputable in cell metabolism and oxidative stress-induced cell death.
In oxidative stress, the enzyme is capable of over-activation by creating huge branching PAR polymers within minutes, thereby depleting the available NAD+ pool of the cells and causing energetic failure [40, 49, 50]. Inhibition of PARP activity prevents necrotic cell death in oxidative stress and promotes cell survival and apoptosis, a favourable cell death form. During apoptosis PARP is inactivated by caspase cleavage that dissociates the DNA binding and catalytic domains of PARP and prevents PARP activation by DNA strand breaks. Apart from caspases, various proteases (cathepsin, calpain, granzyme B) may inactivate PARP by proteolytic cleavage following OGD or hypoxia injury [2]. PARP also catalyzes its self-PARylation and this auto-modification reduces the catalytic activity of the enzyme, thus, it also serves as a control of its activity. It was suggested that other post-translational modifications of the enzyme (phosphorylation, acetylation) are also implicated in the regulation of PARP activity [49, 51].
PARP also regulates gene transcription via interacting with other transcription factors or by directly binding to promoter regions to control cellular metabolism [52, 53]. Among others, the PAR-degrading enzyme PARG, the nuclear NAD+ synthesis enzyme NMNAT-1 and Nuclear Respiratory Factor 1, which activates the expression of metabolic genes regulating cellular growth and mitochondrial respiration, were identified as PARP interactors [53–56]. The interplay between PARP-1 and the NAD+ biosynthesis enzyme NMNAT-1 is particularly interesting because it suggests that under baseline conditions the nuclear NAD+ utilization and recycling are fully coupled processes [54, 57].
PARP activation may cause mitochondrial dysfunction in cells exposed to oxidative stress that is best characterized by reduced mitochondrial reserve capacity [58]. The cellular NAD+ pool is compartmentalized within the cells and since the NAD+ pools are non-exchangeable between the nucleus and the mitochondria [22], the PARP-mediated nuclear NAD+ depletion may develop mitochondrial failure via prior depletion of the cytoplasmic NAD+ pool and inhibition of glycolysis. There seems to be a competition for substrate between PARP-1 and other NAD+ -consuming enzymes including the sirtuins [40, 59]. The sirtuin family members use NAD+ for their deacetylation function and are mainly implicated in the regulation of glucose and lipid metabolism [59, 60]. The various sirtuins show distinct intracellular localization profile, Sirt1, Sirt6 and Sirt7 are predominantly nuclear proteins [59]. While PARP and sirtuins share their common substrate, the NAD+ consumption by sirtuins is hardly comparable to that of PARP, thus competition for substrate has little impact on PARP activity. Still Sirt1 may affect the action of PARP-1 via direct interaction of the two proteins and by modulating PARP activity via deacetylation [61]. On the other hand, the nuclear sirtuins are possibly affected by PARP1-mediated NAD+ consumption under oxidative stress, since the lack of PARP-1 increases Sirt-1 activity and stimulates the mitochondrial metabolism [62]. Thus, it suggests that sirtuins and especially Sirt-1 may play a role in PARP-mediated mitochondrial suppression, as PARP-mediated NAD+ consumption decreases Sirt-1 activity and mitochondrial metabolism.
PARP-1 activation is generally associated with necrotic cell death, but PARP-1 may be involved in other cell death forms. The obligatory trigger of PARP activation is DNA single strand break, which can be induced by a variety of oxidants. In pathophysiological conditions, reactive species capable of inducing DNA strand breakage, and thereby PARP activation, include hydroxyl radical, nitroxyl radical, as well as peroxynitrite (a reactive oxidant produced from the reaction of nitric oxide and superoxide) [63–65]. In response to DNA damage, PARP becomes activated and, using NAD+ as a substrate, catalyzes the building of homopolymers of adenosine diphosphate ribose units. Depending of the severity of DNA damage this process can be overwhelming and it may deplete the cellular NAD+ and ATP pools and can eventually lead to cell death via the necrotic route [39]. Hypoxia- or OGD-reoxygenation injury predisposes the cells to PARP-1 mediated NAD+ depletion: lower level of oxidative stress and PARP-1 activity can exhaust the cellular NAD+ pool and lead to necrosis (Figure 5).
The activation of PARP-1 is a regulated process and the enzyme also plays an important role in programmed cell death forms [66, 67]. PARP-1 activity level depends on the severity of oxidative stress, and its high catalytic activity is necessary to promote immediate DNA repair. This protective mechanism helps maintain genome integrity: the ADP-ribose units provide energy source for base excision repair and the negatively charged polymer recruits other repair proteins to the site of the damage [68]. Low level of PARP activity is always detectable, and it is associated with normal gene expression and physiological maintenance of DNA integrity. Severe DNA damage that occurs under pathological conditions induces excessive activation of the enzyme that can rapidly deplete the cellular NAD+ content. Less severe oxidative damage can induce moderate PARP activation to restore the DNA integrity and if the repair process is unsuccessful, apoptosis may be induced [39, 40, 66]. The apoptotic process follows the intrinsic or mitochondrial pathway in this case [69], and it requires a nuclear-to-mitochondrial signal for initiation. The signalling molecules have not been unequivocally identified, but PARP-1 and the PAR polymer might be directly involved in this process [70]. PARP-1 can generate large PAR polymers that may escape from the nucleus. The PAR polymer itself can induce membrane damage, mitochondrial depolarization and apoptosis-inducing factor (AIF) release [70]. AIF released from the mitochondria translocates to the nucleus and plays a role in cell death progression [71]. This PAR-mediated cell death program is occasionally discriminated from necrosis and apoptosis as parthanatos, a distinct cell death form [70]. Triggering of the mitochondrial apoptotic signal leads to caspase activation, which becomes detectable 1 hour following the start of reoxygenation and remains elevated for several hours in hypoxia-reoxygenation injury [2]. During apoptosis caspase cleavage inactivates PARP-1 by removing the catalytic region of the protein from the DNA binding region to avoid unnecessary NAD+ consumption caused by the fragmented DNA [72].
PARP-1 itself can exit the nucleus in oxidative stress and interact with cytoplasmic or mitochondrial proteins [4]. Thereby, PARP-1 can have direct access to the cytoplasmic or mitochondrial NAD+ pools and can PARylate cytoplasmic and mitochondrial proteins [73]. In this process, the PAR-binding E3 ubiquitin ligase RNF146 (ring finger protein 146, dactylidin also named Iduna) is involved [74–76], which can capture the PARP-1 protein and promote its ubiquitination and proteasomal degradation [4]. RNF146 was discovered as a neuroprotective gene product that when over-expressed exerted protection against NMDA excitotoxicity and MNNG-induced PARP-1 dependent cell death
3.4. Increased sensitivity to oxidative damage
Post-hypoxic cells show increased sensitivity to oxidant-induced cellular injury due to (1) diminished ATP and NAD+ pools, (2) low mitochondrial metabolic output and (3) reduced antioxidant capacity. Hypoxia and glucose deprivation decrease the intracellular concentrations of ATP and NAD+ that greatly reduce the tolerance to cytotoxic injuries since they are associated with enhanced energy consumption. Oxidant-induced cellular damage is further aggravated by the diminished NAD+ and ATP synthesis due to mitochondrial dysfunction and restricted glycolytic capacity. The exposure to low oxygen atmosphere induces down-regulation of antioxidant genes that reduces the buffering capacity during the reoxygenation phase [85, 86]. Changes in oxygen supply are detected via reduced levels of oxidants and hypoxia-inducible factor-α (HIF-1α) is responsible for transcriptional regulation of the antioxidant enzymes [87, 88]. The diminished scavenging capability and the higher oxidant generation during the recovery period greatly reduce the tolerance to oxidants. Overall, these factors increase the vulnerability of the cells and oxidants can induce devastating damage during the reoxygenation period.
The cells may be treated with exogenous oxidants following the
4. Interventions to increase the recovery following hypoxia-reoxygenation or OGD-reoxygenation injury
In drug discovery, the ultimate goal of using
Interventions that reduce the cellular damage in hypoxia-reoxygenation injury and enhance recovery following hypoxia or OGD exposure may target (1) the metabolism and energy resources, (2) the oxidative stress pathways and antioxidant responses or (3) the proteasome and proteolytic activity. Apart from these universal cellular targets, some tissue-specific receptors were also found to have beneficial effects in some models. Energy replenishment using adenosine or inosine is effective in various cell types exposed to OGD injury since the pentose part of these nucleosides can be anaerobically metabolized through the pentose phosphate pathway [1–3]. Purine nucleosides are preferable to glucose in hypoxia since their metabolism can produce more ATP molecules than glycolysis and their utilization is more effective at low concentrations. Furthermore, they possess anti-inflammatory and weak PARP inhibitor activity that supports their activity
5. Conclusion
The hypoxia-reoxygenation model is a valuable tool in hypoxia and ischemia research that may be combined with other injury models to fully reproduce features of inflammatory and vascular diseases. This low-cost model does not require advanced research skills and may be optimized within a short time in the laboratory. The cellular damage mostly occurs as a consequence of energetic failure and shows necrotic characteristics in this model. Both the hypoxic phase and the post-hypoxic recovery period involve massive changes in the cellular metabolism: a characteristic suppression of mitochondrial energy production is caused by the lack of oxygen and later by the shortage of NAD+ supply. The recovery from this state is a delicate process that recreates the balance in cellular energetics.
Acknowledgments
D.G. received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme under the grant agreement number 628100.
References
- 1.
Modis K, Gero D, Nagy N, Szoleczky P, Toth ZD, Szabo C. Cytoprotective effects of adenosine and inosine in an in vitro model of acute tubular necrosis. British Journal of Pharmacology. 2009;158(6):1565–1578. doi: 10.1111/j.1476-5381.2009.00432.x. PubMed PMID: 19906119; PubMed Central PMCID: PMC2795223. - 2.
Szoleczky P, Modis K, Nagy N, Dori Toth Z, DeWitt D, Szabo C, et al. Identification of agents that reduce renal hypoxia-reoxygenation injury using cell-based screening: purine nucleosides are alternative energy sources in LLC-PK1 cells during hypoxia. Archives of Biochemistry and Biophysics. 2012;517(1):53–70. Epub 2011/11/22. doi: 10.1016/j.abb.2011.11.005. PubMed PMID: 22100704. - 3.
Modis K, Gero D, Stangl R, Rosero O, Szijarto A, Lotz G, et al. Adenosine and inosine exert cytoprotective effects in an in vitro model of liver ischemia-reperfusion injury. International Journal of Molecular Medicine. 2013;31(2):437–446. doi: 10.3892/ijmm.2012.1203. PubMed PMID: 23232950; PubMed Central PMCID: PMC3981016. - 4.
Gero D, Szoleczky P, Chatzianastasiou A, Papapetropoulos A, Szabo C. Modulation of poly(ADP-ribose) polymerase-1 (PARP-1)-mediated oxidative cell injury by ring finger protein 146 (RNF146) in cardiac myocytes. Molecular Medicine. 2014;20:313–328. doi: 10.2119/molmed.2014.00102. PubMed PMID: 24842055; PubMed Central PMCID: PMC4153837. - 5.
Gero D, Szabo C. Salvage of nicotinamide adenine dinucleotide plays a critical role in the bioenergetic recovery of post-hypoxic cardiomyocytes. British Journal of Pharmacology. 2015;172(20):4817–4832. doi: 10.1111/bph.13252. PubMed PMID: 26218637; PubMed Central PMCID: PMC4621988. - 6.
Lemasters JJ, Oliver C. Cell Biology of Trauma. Boca Raton, FL: CRC Press; 1995. 367 p. - 7.
Wu D, Yotnda P. Induction and testing of hypoxia in cell culture. Journal of Visualized Experiments. 2011;54(e2899). doi: 10.3791/2899. PubMed PMID: 21860378; PubMed Central PMCID: PMC3217626. - 8.
Roemgens A, Singh S, Beyer C, Arnold S. Inducers of chemical hypoxia act in a gender- and brain region-specific manner on primary astrocyte viability and cytochrome C oxidase. Neurotoxicity Research. 2011;20(1):1–14. doi: 10.1007/s12640-010-9213-z. PubMed PMID: 20734249. - 9.
Ren L, Liu W, Wang Y, Wang JC, Tu Q, Xu J, et al. Investigation of hypoxia-induced myocardial injury dynamics in a tissue interface mimicking microfluidic device. Analytical Chemistry. 2013;85(1):235–244. doi: 10.1021/ac3025812. PubMed PMID: 23205467. - 10.
Szabo G, Veres G, Radovits T, Gero D, Modis K, Miesel-Groschel C, et al. Cardioprotective effects of hydrogen sulfide. Nitric Oxide: Biology and Chemistry/Official Journal of the Nitric Oxide Society. 2011;25(2):201–210. Epub 2010/11/26. doi: 10.1016/j.niox.2010.11.001. PubMed PMID: 21094267; PubMed Central PMCID: PMC3139695. - 11.
Hotter G, Palacios L, Sola A. Low O2 and high CO2 in LLC-PK1 cells culture mimics renal ischemia-induced apoptosis. Laboratory Investigation; a Journal of Technical Methods and Pathology. 2004;84(2):213–220. doi: 10.1038/labinvest.3700026. PubMed PMID: 14688798. - 12.
Hinkle PC. P/O ratios of mitochondrial oxidative phosphorylation. Biochimica et Biophysica Acta. 2005;1706(1–2):1–11. doi: 10.1016/j.bbabio.2004.09.004. PubMed PMID: 15620362. - 13.
Brand MD. The efficiency and plasticity of mitochondrial energy transduction. Biochemical Society Transactions. 2005;33(Pt 5):897–904. doi: 10.1042/BST20050897. PubMed PMID: 16246006. - 14.
Buono MJ, Kolkhorst FW. Estimating ATP resynthesis during a marathon run: a method to introduce metabolism. Advances in Physiology Education. 2001;25:70–71. - 15.
Massudi H, Grant R, Guillemin GJ, Braidy N. NAD+ metabolism and oxidative stress: the golden nucleotide on a crown of thorns. Redox Report. 2012;17(1):28–46. Epub 2012/02/22. doi: 10.1179/1351000212Y.0000000001. PubMed PMID: 22340513. - 16.
Chiarugi A, Dolle C, Felici R, Ziegler M. The NAD metabolome—a key determinant of cancer cell biology. Nature Reviews Cancer. 2012;12(11):741–752. Epub 2012/09/29. doi: 10.1038/nrc3340. PubMed PMID: 23018234. - 17.
Houtkooper RH, Canto C, Wanders RJ, Auwerx J. The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. Endocrine Reviews. 2010;31(2):194–223. Epub 2009/12/17. doi: 10.1210/er.2009-0026. PubMed PMID: 20007326; PubMed Central PMCID: PMC2852209. - 18.
Hassa PO, Haenni SS, Elser M, Hottiger MO. Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Microbiology and Molecular Biology Reviews. 2006;70(3):789–829. Epub 2006/09/09. doi: 10.1128/MMBR.00040-05. PubMed PMID: 16959969; PubMed Central PMCID: PMC1594587. - 19.
Hirschey MD. Old enzymes, new tricks: sirtuins are NAD(+)-dependent de-acylases. Cell Metabolism. 2011;14(6):718–719. Epub 2011/11/22. doi: 10.1016/j.cmet.2011.10.006. PubMed PMID: 22100408; PubMed Central PMCID: PMC3830953. - 20.
Rongvaux A, Andris F, Van Gool F, Leo O. Reconstructing eukaryotic NAD metabolism. Bioessays. 2003;25(7):683–690. Epub 2003/06/20. doi: 10.1002/bies.10297. PubMed PMID: 12815723. - 21.
Berger F, Lau C, Dahlmann M, Ziegler M. Subcellular compartmentation and differential catalytic properties of the three human nicotinamide mononucleotide adenylyltransferase isoforms. Journal of Biological Chemistry. 2005;280(43):36334–36341. Epub 2005/08/25. doi: M508660200 [pii] 10.1074/jbc.M508660200. PubMed PMID: 16118205. - 22.
Nikiforov A, Dolle C, Niere M, Ziegler M. Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracellular precursors to mitochondrial NAD generation. Journal of Biological Chemistry. 2012;286(24):21767–21778. Epub 2011/04/21. doi: M110.213298 [pii] 10.1074/jbc.M110.213298. PubMed PMID: 21504897; PubMed Central PMCID: PMC3122232. - 23.
Liaudet L, Szabo G, Szabo C. Oxidative stress and regional ischemia-reperfusion injury: the peroxynitrite-poly(ADP-ribose) polymerase connection. Coronary Artery Disease. 2003;14(2):115–122. doi: 10.1097/01.mca.0000060943.08352.b7. PubMed PMID: 12655275. - 24.
Szabo G, Liaudet L, Hagl S, Szabo C. Poly(ADP-ribose) polymerase activation in the reperfused myocardium. Cardiovascular Research. 2004;61(3):471–480. doi: 10.1016/j.cardiores.2003.09.029. PubMed PMID: 14962478. - 25.
Szabo G, Soos P, Bahrle S, Zsengeller Z, Flechtenmacher C, Hagl S, et al. Role of poly(ADP-ribose) polymerase activation in the pathogenesis of cardiopulmonary dysfunction in a canine model of cardiopulmonary bypass. European Journal of Cardiothorac Surgery. 2004;25(5):825–832. Epub 2004/04/15. doi: 10.1016/j.ejcts.2004.01.031. PubMed PMID: 15082289. - 26.
Rousset S, Alves-Guerra MC, Mozo J, Miroux B, Cassard-Doulcier AM, Bouillaud F, et al. The biology of mitochondrial uncoupling proteins. Diabetes. 2004;53(Suppl. 1):S130–S135. PubMed PMID: 14749278. - 27.
Gero D, Szabo C. Glucocorticoids suppress mitochondrial oxidant production via upregulation of uncoupling protein 2 in hyperglycemic endothelial cells. PloS One. 2016;11(4):e0154813. doi: 10.1371/journal.pone.0154813. PubMed PMID: 27128320. PubMed Central PMCID: PMC4851329. - 28.
Mailloux RJ, Harper ME. Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radical Biology and Medicine. 2011;51(6):1106–1115. doi: 10.1016/j.freeradbiomed.2011.06.022. PubMed PMID: 21762777. - 29.
Pecqueur C, Alves-Guerra MC, Gelly C, Levi-Meyrueis C, Couplan E, Collins S, et al. Uncoupling protein 2, in vivo distribution, induction upon oxidative stress, and evidence for translational regulation. Journal of Biological Chemistry. 2001;276(12):8705–8712. doi: 10.1074/jbc.M006938200. PubMed PMID: 11098051. - 30.
Lenaz G. The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life. 2001;52(3–5):159–164. doi: 10.1080/15216540152845957. PubMed PMID: 11798028. - 31.
Lenaz G, Baracca A, Barbero G, Bergamini C, Dalmonte ME, Del Sole M, et al. Mitochondrial respiratory chain super-complex I-III in physiology and pathology. Biochimica et Biophysica Acta. 2010;1797(6–7):633–640. doi: 10.1016/j.bbabio.2010.01.025. PubMed PMID: 20116362. - 32.
Quijano C, Castro L, Peluffo G, Valez V, Radi R. Enhanced mitochondrial superoxide in hyperglycemic endothelial cells: direct measurements and formation of hydrogen peroxide and peroxynitrite. American Journal of Physiology Heart and Circulatory Physiology. 2007;293(6):H3404–H3414. doi: 10.1152/ajpheart.00761.2007. PubMed PMID: 17906108. - 33.
Turrens JF. Mitochondrial formation of reactive oxygen species. Journal of Physiology. 2003;552(Pt 2):335–344. doi: 10.1113/jphysiol.2003.049478. PubMed PMID: 14561818. PubMed Central PMCID: PMC2343396. - 34.
Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615–1625. PubMed PMID: 15919781. - 35.
Korshunov SS, Skulachev VP, Starkov AA. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS Letters. 1997;416(1):15–18. PubMed PMID: 9369223. - 36.
Suski JM, Lebiedzinska M, Bonora M, Pinton P, Duszynski J, Wieckowski MR. Relation Between Mitochondrial Membrane Potential and ROS Formation. In: Palmeira CM, Moreno AJ, editors. Mitochondrial Bioenergetics: Methods and Protocols Methods in Molecular Biology. Springer Science + Business Media, LLC New York, NY; 2012. Vol. 810, pp. 183–205. - 37.
Suzuki K, Olah G, Modis K, Coletta C, Kulp G, Gero D, et al. Hydrogen sulfide replacement therapy protects the vascular endothelium in hyperglycemia by preserving mitochondrial function. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(33):13829–13834. doi: 10.1073/pnas.1105121108. PubMed PMID: 21808008. PubMed Central PMCID: PMC3158211. - 38.
Mailloux RJ, Seifert EL, Bouillaud F, Aguer C, Collins S, Harper ME. Glutathionylation acts as a control switch for uncoupling proteins UCP2 and UCP3. Journal of Biological Chemistry. 2011;286(24):21865–21875. doi: 10.1074/jbc.M111.240242. PubMed PMID: 21515686; PubMed Central PMCID: PMC3122241. - 39.
Gero D, Szabo C. Role of the peroxynitrite-poly (ADP-ribose) polymerase pathway in the pathogenesis of liver injury. Current Pharmceutical Design. 2006;12(23):2903–2910. PubMed PMID: 16918420. - 40.
Gero D, Szabo C. Poly(ADP-ribose) polymerase: a new therapeutic target? Current Opinion in Anaesthesiology. 2008;21(2):111–121. doi: 10.1097/ACO.0b013e3282f63c15. PubMed PMID: 18443476. - 41.
Molnar A, Toth A, Bagi Z, Papp Z, Edes I, Vaszily M, et al. Activation of the poly(ADP-ribose) polymerase pathway in human heart failure. Molecular Medicine. 2006;12(7–8):143–152. Epub 2006/11/08. doi: 10.2119/2006-00043.Molnar. PubMed PMID: 17088946. PubMed Central PMCID: PMC1626594. - 42.
Piskunova TS, Yurova MN, Ovsyannikov AI, Semenchenko AV, Zabezhinski MA, Popovich IG, et al. Deficiency in poly(ADP-ribose) polymerase-1 (PARP-1) accelerates aging and spontaneous carcinogenesis in mice. Current Gerontology and Geriatrics Research. Volume 2008:754190. Epub 2008/01/01. doi: 10.1155/2008/754190. PubMed PMID: 19415146; PubMed Central PMCID: PMC2672038. - 43.
Hur JW, Sung YK, Shin HD, Park BL, Cheong HS, Bae SC. Poly(ADP-ribose) polymerase (PARP) polymorphisms associated with nephritis and arthritis in systemic lupus erythematosus. Rheumatology (Oxford). 2006;45(6):711–717. Epub 2006/02/08. doi: kei262 [pii] 10.1093/rheumatology/kei262. PubMed PMID: 16461442. - 44.
Cottet F, Blanche H, Verasdonck P, Le Gall I, Schachter F, Burkle A, et al. New polymorphisms in the human poly(ADP-ribose) polymerase-1 coding sequence: lack of association with longevity or with increased cellular poly(ADP-ribosyl)ation capacity. Journal of Molecular Medicine (Berl). 2000;78(8):431–440. Epub 2000/11/30. PubMed PMID: 11097112. - 45.
Lockett KL, Hall MC, Xu J, Zheng SL, Berwick M, Chuang SC, et al. The ADPRT V762A genetic variant contributes to prostate cancer susceptibility and deficient enzyme function. Cancer Research. 2004;64(17):6344–6348. Epub 2004/09/03. doi: 10.1158/0008-5472.CAN-04-033864/17/6344 [pii]. PubMed PMID: 15342424. - 46.
Roszak A, Lianeri M, Sowinska A, Jagodzinski PP. Involvement of PARP-1 Val762Ala polymorphism in the onset of cervical cancer in Caucasian women. Molecular Diagnosis and Therapy. 2013;17(4):239?245 Epub 2013/05/02. doi: 10.1007/s40291-013-0036-5. PubMed PMID: 23633189. - 47.
Huber A, Bai P, de Murcia JM, de Murcia G. PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development. DNA Repair (Amst). 2004;3(8–9):1103–1108. Epub 2004/07/29. doi: 10.1016/j.dnarep.2004.06.002S1568786404001764 [pii]. PubMed PMID: 15279798. - 48.
Boehler C, Gauthier LR, Mortusewicz O, Biard DS, Saliou JM, Bresson A, et al. Poly(ADP-ribose) polymerase 3 (PARP3), a newcomer in cellular response to DNA damage and mitotic progression. Proceedings of the National Academy of Sciences of the United States of America 2011; 108(7):2783–2788. Epub 2011/01/29. doi: 1016574108 [pii] 10.1073/pnas.1016574108. PubMed PMID: 21270334; PubMed Central PMCID: PMC3041075. - 49.
Luo X, Kraus WL. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Development. 2012;26(5):417–432. Epub 2012/03/07. doi: 26/5/417 [pii] 10.1101/gad.183509.111. PubMed PMID: 22391446. PubMed Central PMCID: PMC3305980. - 50.
Kim MY, Zhang T, Kraus WL. Poly(ADP-ribosyl)ation by PARP-1: 'PAR-laying' NAD+ into a nuclear signal. Genes Development. 2005;19(17):1951–1967. Epub 2005/09/06. doi: 19/17/1951 [pii] 10.1101/gad.1331805. PubMed PMID: 16140981. - 51.
Brunyanszki A, Olah G, Coletta C, Szczesny B, Szabo C. Regulation of mitochondrial poly(ADP-Ribose) polymerase activation by the beta-adrenoceptor/cAMP/protein kinase A axis during oxidative stress. Molecular Pharmacology. 2014;86(4):450–462. doi: 10.1124/mol.114.094318. PubMed PMID: 25069723. PubMed Central PMCID: PMC4164979. - 52.
Krishnakumar R, Gamble MJ, Frizzell KM, Berrocal JG, Kininis M, Kraus WL. Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes. Science. 2008;319(5864):819–821. doi: 10.1126/science.1149250. PubMed PMID: 18258916. - 53.
Kraus WL. Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation. Current Opinion in Cell Biology. 2008;20(3):294–302. doi: 10.1016/j.ceb.2008.03.006. PubMed PMID: 18450439. PubMed Central PMCID: PMC2518631. - 54.
Zhang T, Berrocal JG, Yao J, DuMond ME, Krishnakumar R, Ruhl DD, et al. Regulation of poly(ADP-ribose) polymerase-1-dependent gene expression through promoter-directed recruitment of a nuclear NAD+ synthase. Journal of Biological Chemistry. 2012;287(15):12405–12416. doi: 10.1074/jbc.M111.304469. PubMed PMID: 22334709. PubMed Central PMCID: PMC3320990. - 55.
Hossain MB, Ji P, Anish R, Jacobson RH, Takada S. Poly(ADP-ribose) polymerase 1 interacts with nuclear respiratory factor 1 (NRF-1) and plays a role in NRF-1 transcriptional regulation. Journal of Biological Chemistry. 2009;284(13):8621–8632. Epub 2009/02/03. doi: M807198200 [pii] 10.1074/jbc.M807198200. PubMed PMID: 19181665. PubMed Central PMCID: PMC2659221. - 56.
Frizzell KM, Gamble MJ, Berrocal JG, Zhang T, Krishnakumar R, Cen Y, et al. Global analysis of transcriptional regulation by poly(ADP-ribose) polymerase-1 and poly(ADP-ribose) glycohydrolase in MCF-7 human breast cancer cells. Journal of Biological Chemistry. 2009;284(49):33926–33938. Epub 2009/10/09. doi: M109.023879 [pii] 10.1074/jbc.M109.023879. PubMed PMID: 19812418. PubMed Central PMCID: PMC2797163. - 57.
Berger F, Lau C, Ziegler M. Regulation of poly(ADP-ribose) polymerase 1 activity by the phosphorylation state of the nuclear NAD biosynthetic enzyme NMN adenylyl transferase 1. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(10):3765–3770. doi: 10.1073/pnas.0609211104. PubMed PMID: 17360427. PubMed Central PMCID: PMC1820658. - 58.
Modis K, Gero D, Erdelyi K, Szoleczky P, DeWitt D, Szabo C. Cellular bioenergetics is regulated by PARP1 under resting conditions and during oxidative stress. Biochemical Pharmacology. 2012;83(5):633–643. Epub 2011/12/27. doi: 10.1016/j.bcp.2011.12.014. PubMed PMID: 22198485. PubMed Central PMCID: PMC3272837. - 59.
Sack MN, Finkel T. Mitochondrial metabolism, sirtuins, and aging. Cold Spring Harbor Perspectives in Biology. 2012;4(12):1-10 doi: 10.1101/cshperspect.a013102. PubMed PMID: 23209156. PubMed Central PMCID: PMC3504438. - 60.
Houtkooper RH, Pirinen E, Auwerx J. Sirtuins as regulators of metabolism and healthspan. Nature Reviews Molecular Cell Biology. 2012;13(4):225–238. Epub 2012/03/08. doi: nrm3293 [pii] 10.1038/nrm3293. PubMed PMID: 22395773. - 61.
Rajamohan SB, Pillai VB, Gupta M, Sundaresan NR, Birukov KG, Samant S, et al. SIRT1 promotes cell survival under stress by deacetylation-dependent deactivation of poly(ADP-ribose) polymerase 1. Molecular and Cellular Biology. 2009;29(15):4116–4129. Epub 2009/05/28. doi: MCB.00121-09 [pii] 10.1128/MCB.00121-09. PubMed PMID: 19470756. PubMed Central PMCID: PMC2715814. - 62.
Bai P, Canto C, Oudart H, Brunyanszki A, Cen Y, Thomas C, et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metabolism. 2011;13(4):461–468. Epub 2011/04/05. doi: 10.1016/j.cmet.2011.03.004. PubMed PMID: 21459330. PubMed Central PMCID: PMC3086520. - 63.
Berger NA. Oxidant-induced cytotoxicity: a challenge for metabolic modulation. American Journal of Respiratory Cell and Molecular Biology. 1991;4(1):1–3. doi: 10.1165/ajrcmb/4.1.1. PubMed PMID: 1898851. - 64.
Lautier D, Lagueux J, Thibodeau J, Menard L, Poirier GG. Molecular and biochemical features of poly (ADP-ribose) metabolism. Molecular and Cellular Biochemistry. 1993;122(2):171–193. PubMed PMID: 8232248. - 65.
Ueda K, Hayaishi O. ADP-ribosylation. Annual Review of Biochemistry. 1985;54:73–100. doi: 10.1146/annurev.bi.54.070185.000445. PubMed PMID: 3927821. - 66.
Virag L. PARP-1 and the Shape of Cell Death. In: Bürkle A, editor. Poly(ADP-Ribosyl)ation. New York: Springer US; 2006. pp. 141–152. - 67.
Jagtap P, Szabo C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nature Reviews Drug Discovery. 2005;4(5):421–440. Epub 2005/05/03. doi: 10.1038/nrd1718. PubMed PMID: 15864271. - 68.
Malanga M, Althaus FR. The role of poly(ADP-ribose) in the DNA damage signaling network. Biochemistry and Cell Biology. 2005;83(3):354–364. doi: 10.1139/o05-038. PubMed PMID: 15959561. - 69.
Elmore S. Apoptosis: a review of programmed cell death. Toxicologic Pathology. 2007;35(4):495–516. doi: 10.1080/01926230701320337. PubMed PMID: 17562483. PubMed Central PMCID: PMC2117903. - 70.
Yu SW, Andrabi SA, Wang H, Kim NS, Poirier GG, Dawson TM, et al. Apoptosis-inducing factor mediates poly(ADP-ribose) (PAR) polymer-induced cell death. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(48):18314–18319. doi: 10.1073/pnas.0606528103. PubMed PMID: 17116881. PubMed Central PMCID: PMC1838748. - 71.
Chen M, Zsengeller Z, Xiao CY, Szabo C. Mitochondrial-to-nuclear translocation of apoptosis-inducing factor in cardiac myocytes during oxidant stress: potential role of poly(ADP-ribose) polymerase-1. Cardiovascular Research. 2004;63(4):682–688. doi: 10.1016/j.cardiores.2004.04.018. PubMed PMID: 15306224. - 72.
Duriez PJ, Shah GM. Cleavage of poly(ADP-ribose) polymerase: a sensitive parameter to study cell death. Biochemistry and Cell Biology. 1997;75(4):337–349. PubMed PMID: 9493956. - 73.
Du L, Zhang X, Han YY, Burke NA, Kochanek PM, Watkins SC, et al. Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress. Journal of Biological Chemistry. 2003;278(20):18426–18433. Epub 2003/03/11. doi: 10.1074/jbc.M301295200M301295200 [pii]. PubMed PMID: 12626504. - 74.
Zhang Y, Liu S, Mickanin C, Feng Y, Charlat O, Michaud GA, et al. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nature Cell Biology. 2011;13(5):623–629. Epub 2011/04/12. doi: ncb2222 [pii] 10.1038/ncb2222. PubMed PMID: 21478859. - 75.
Zhou ZD, Chan CH, Xiao ZC, Tan EK. Ring finger protein 146/Iduna is a poly(ADP-ribose) polymer binding and PARsylation dependent E3 ubiquitin ligase. Cell Adhesion and Migration. 2011;5(6):463–471. Epub 2012/01/26. doi: 18356 [pii] 10.4161/cam.5.6.18356. PubMed PMID: 22274711. PubMed Central PMCID: PMC3277779. - 76.
Wang Z, Michaud GA, Cheng Z, Zhang Y, Hinds TR, Fan E, et al. Recognition of the iso-ADP-ribose moiety in poly(ADP-ribose) by WWE domains suggests a general mechanism for poly(ADP-ribosyl)ation-dependent ubiquitination. Genes Development. 2012;26(3):235–240. Epub 2012/01/24. doi: gad.182618.111 [pii] 10.1101/gad.182618.111. PubMed PMID: 22267412; PubMed Central PMCID: PMC3278890. - 77.
Dawson VL, editor Symposium S14: stroke: inflammation in the neurovascular unit, ischemic preconditioning. Journal of Neurochemistry, 2004;90 (Suppl. 1): p80. - 78.
Andrabi SA, Kang HC, Haince JF, Lee YI, Zhang J, Chi Z, et al. Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death. Nature Medicine. 2011;17(6):692–699. Epub 2011/05/24. doi: nm.2387 [pii] 10.1038/nm.2387. PubMed PMID: 21602803. - 79.
Kang HC, Lee YI, Shin JH, Andrabi SA, Chi Z, Gagne JP, et al. Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(34):14103–14108. Epub 2011/08/10. doi: 1108799108 [pii] 10.1073/pnas.1108799108. PubMed PMID: 21825151; PubMed Central PMCID: PMC3161609. - 80.
Jungmichel S, Rosenthal F, Altmeyer M, Lukas J, Hottiger MO, Nielsen ML. Proteome-wide identification of poly(ADP-Ribosyl)ation targets in different genotoxic stress responses. Molecular Cell. 2013;52(2):272–285. doi: 10.1016/j.molcel.2013.08.026. PubMed PMID: 24055347. - 81.
Rossi MN, Carbone M, Mostocotto C, Mancone C, Tripodi M, Maione R, et al. Mitochondrial localization of PARP-1 requires interaction with mitofilin and is involved in the maintenance of mitochondrial DNA integrity. Journal of Biological Chemistry. 2009;284(46):31616–31624. Epub 2009/09/19. doi: M109.025882 [pii] 10.1074/jbc.M109.025882. PubMed PMID: 19762472. PubMed Central PMCID: PMC2797232. - 82.
Lapucci A, Pittelli M, Rapizzi E, Felici R, Moroni F, Chiarugi A. Poly(ADP-ribose) polymerase-1 is a nuclear epigenetic regulator of mitochondrial DNA repair and transcription. Molecular Pharmacology. 2011;79(6):932–940. Epub 2011/03/29. doi: mol.110.070110 [pii] 10.1124/mol.110.070110. PubMed PMID: 21441600. - 83.
Horvath EM, Szabo C. Poly(ADP-ribose) polymerase as a drug target for cardiovascular disease and cancer: an update. Drug News Perspectives. 2007;20(3):171–181. Epub 2007/05/24. doi: 1092098 [pii] 10.1358/dnp.2007.20.3.1092098. PubMed PMID: 17520094. - 84.
Pacher P, Szabo C. Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovascular Drug Reviews. 2007;25(3):235–260. Epub 2007/10/09. doi: CDR018 [pii] 10.1111/j.1527-3466.2007.00018.x. PubMed PMID: 17919258. PubMed Central PMCID: PMC2225457. - 85.
Gao YH, Li CX, Shen SM, Li H, Chen GQ, Wei Q, et al. Hypoxia-inducible factor 1alpha mediates the down-regulation of superoxide dismutase 2 in von Hippel-Lindau deficient renal clear cell carcinoma. Biochemical and Biophysical Research Communications. 2013;435(1):46–51. doi: 10.1016/j.bbrc.2013.04.034. PubMed PMID: 23611775. - 86.
Xi H, Gao YH, Han DY, Li QY, Feng LJ, Zhang W, et al. Hypoxia inducible factor-1alpha suppresses peroxiredoxin 3 expression to promote proliferation of CCRCC cells. FEBS Letters. 2014;588(18):3390–3394. doi: 10.1016/j.febslet.2014.07.030. PubMed PMID: 25093297. - 87.
Brune B, Zhou J. The role of nitric oxide (NO) in stability regulation of hypoxia inducible factor-1alpha (HIF-1alpha). Current Medicinal Chemistry. 2003;10(10):845–855. PubMed PMID: 12678687. - 88.
Ratcliffe PJ, O'Rourke JF, Maxwell PH, Pugh CW. Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. The Journal of Experimental Biology. 1998;201(Pt 8):1153–1162. PubMed PMID: 9510527. - 89.
Zingarelli B, Cuzzocrea S, Zsengeller Z, Salzman AL, Szabo C. Protection against myocardial ischemia and reperfusion injury by 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase. Cardiovascular Research. 1997;36(2):205–215. Epub 1998/02/17. PubMed PMID: 9463632. - 90.
Kovacs K, Toth A, Deres P, Kalai T, Hideg K, Gallyas F, Jr., et al. Critical role of PI3-kinase/Akt activation in the PARP inhibitor induced heart function recovery during ischemia-reperfusion. Biochemical Pharmacology. 2006;71(4):441–452. Epub 2005/12/13. doi: 10.1016/j.bcp.2005.05.036. PubMed PMID: 16337154. - 91.
Roesner JP, Mersmann J, Bergt S, Bohnenberg K, Barthuber C, Szabo C, et al. Therapeutic injection of PARP inhibitor INO-1001 preserves cardiac function in porcine myocardial ischemia and reperfusion without reducing infarct size. Shock. 2010;33(5):507–512. Epub 2010/04/17. doi: 10.1097/SHK.0b013e3181c4fb08. PubMed PMID: 20395771. - 92.
Desestret V, Riou A, Chauveau F, Cho TH, Devillard E, Marinescu M, et al. In vitro and in vivo models of cerebral ischemia show discrepancy in therapeutic effects of M2 macrophages. PloS One. 2013;8(6):e67063. doi: 10.1371/journal.pone.0067063. PubMed PMID: 23825621. PubMed Central PMCID: PMC3692438. - 93.
Pugsley MK. Cardiac Drug Development Guide. Totowa, NJ: Humana Press; 2003. x, 431 p. - 94.
Szabo C, Gero D, Hasko G. Anti-Inflammatory and Cytoprotective Effects of Inosine. In: Haskó G, Cronstein BN, Szabó C, editors. Adenosine Receptors: Therapeutic Aspects for Inflammatory and Immune Diseases. Boca Raton, FL: CRC/Taylor & Francis; 2007. pp. 237–256. - 95.
Yamada J, Yoshimura S, Yamakawa H, Sawada M, Nakagawa M, Hara S, et al. Cell permeable ROS scavengers, Tiron and Tempol, rescue PC12 cell death caused by pyrogallol or hypoxia/reoxygenation. Neuroscience Research. 2003;45(1):1–8. PubMed PMID: 12507718. - 96.
Martinez-Romero R, Canuelo A, Martinez-Lara E, Javier Oliver F, Cardenas S, Siles E. Poly(ADP-ribose) polymerase-1 modulation of in vivo response of brain hypoxia-inducible factor-1 to hypoxia/reoxygenation is mediated by nitric oxide and factor inhibiting HIF. Journal of Neurochemistry. 2009;111(1):150–159. doi: 10.1111/j.1471-4159.2009.06307.x. PubMed PMID: 19656264. - 97.
Zhang Y, Zhang X, Park TS, Gidday JM. Cerebral endothelial cell apoptosis after ischemia-reperfusion: role of PARP activation and AIF translocation. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2005;25(7):868–877. doi: 10.1038/sj.jcbfm.9600081. PubMed PMID: 15729291. - 98.
Pashevin DO, Nagibin VS, Tumanovska LV, Moibenko AA, Dosenko VE. Proteasome inhibition diminishes the formation of neutrophil extracellular traps and prevents the death of cardiomyocytes in coculture with activated neutrophils during anoxia-reoxygenation. Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology. 2015;82(6):290–298. doi: 10.1159/000440982. PubMed PMID: 26558384. - 99.
Tang L, Peng Y, Xu T, Yi X, Liu Y, Luo Y, et al. The effects of quercetin protect cardiomyocytes from A/R injury is related to its capability to increasing expression and activity of PKCepsilon protein. Molecular and Cellular Biochemistry. 2013;382(1–2):145–152. doi: 10.1007/s11010-013-1729-0. PubMed PMID: 23793725.