Biomedical subjects

Gabriel G Haddad

Publications and source records attributed to Gabriel G Haddad.

At least 19 recordsLinked to original sources

PubMed2022

Heterozygous Tropomodulin 3 mice have improved lung vascularization after chronic hypoxia.

The molecular mechanisms leading to high-altitude pulmonary hypertension (HAPH) remains poorly understood. We previously analyzed the whole genome sequence of Kyrgyz highland population and identified eight genomic intervals having a potential role in HAPH. Tropomodulin 3 gene (TMOD3), which encodes a protein that binds and caps the pointed ends of actin filaments and inhibits cell migration, was one of the top candidates. Here we systematically sought additional evidence to validate the functional role of TMOD3. In-silico analysis reveals that some of the SNPs in HAPH associated genomic intervals were positioned in a regulatory region that could result in alternative splicing of TMOD3. In order to functionally validate the role of TMOD3 in HAPH, we exposed Tmod3-/+ mice to 4 weeks of constant hypoxia, i.e. 10% O2 and analyzed both functional (hemodynamic measurements) and structural (angiography) parameters related to HAPH. The hemodynamic measurements, such as right ventricular systolic pressure, a surrogate measure for pulmonary arterial systolic pressure, and right ventricular contractility (RV- ± dP/dt), increases with hypoxia did not separate between Tmod3-/+ and control mice. Remarkably, there was a significant increase in the number of lung vascular branches and total length of pulmonary vascular branches (P < 0.001) in Tmod3-/+ after 4 weeks of constant hypoxia as compared with controls. Notably, the Tmod3-/+ endothelial cells migration was also significantly higher than that from the wild-type littermates. Our results indicate that, under chronic hypoxia, lower levels of Tmod3 play an important role in the maintenance or neo-vascularization of pulmonary arteries.

Actin Cytoskeleton↗

PubMed2007

Factors influencing cell fate in the infarct rim.

In focal ischemia, the fate of penumbral cells is closely linked to the infarcted tissue. Because of the release of cytosolic material from damaged cells, the biochemical and ionic alterations within the core are dramatic. Hence, adjacent cells ( infarct rim) are generally exposed to these changes and may be deleteriously affected. To mimic such conditions in vitro, we have employed a slice culture system and used an ischemic solution (IS) that resembles the milieu in the territory of infarct rim. In contrast to normal artificial cerebral spinal fluid, IS is characterized by low O(2), glucose, pH; excitotoxic levels of glutamate; and ionic alterations. In organotypic hippocampal slice cultures, we examined cell injury/death using propidium iodide following exposure to IS. Our data show significant cell injury starting at approximately 8 h following IS exposure with cell injury spreading as a function of exposure duration. We further studied the effect of each component in the IS separately, i.e., acidosis, hypoxia, ionic shifts or glutamate exitotoxicity and were able to isolate the contribution of each of these effectors to the IS-induced cell death. Our results suggest that in IS, acidosis exacerbates the potential for injury while ionic shifts, especially those of K(+) and Na(+), alleviate the potential for cell death.

Animals↗

PubMed2007

Chronic high-inspired CO2 decreases excitability of mouse hippocampal neurons.

To examine the effect of chronically elevated CO(2) on excitability and function of neurons, we exposed mice to 8 and 12% CO(2) for 4 wk (starting at 2 days of age), and examined the properties of freshly dissociated hippocampal neurons obtained from slices. Chronic CO(2)-treated neurons (CC) had a similar input resistance (R(m)) and resting membrane potential (V(m)) as control (CON). Although treatment with 8% CO(2) did not change the rheobase (64 +/- 11 pA, n = 9 vs. 47 +/- 12 pA, n = 8 for CC 8% vs. CON; means +/- SE), 12% CO(2) treatment increased it significantly (73 +/- 8 pA, n = 9, P = 0.05). Furthermore, the 12% CO(2) but not the 8% CO(2) treatment decreased the Na(+) channel current density (244 +/- 36 pA/pF, n = 17, vs. 436 +/- 56 pA/pF, n = 18, for CC vs. CON, P = 0.005). Recovery from inactivation was also lowered by 12% but not 8% CO(2). Other gating properties of Na(+) current, such as voltage-conductance curve, steady-state inactivation, and time constant for deactivation, were not modified by either treatment. Western blot analysis showed that the expression of Na(+) channel types I-III was not changed by 8% CO(2) treatment, but their expression was significantly decreased by 20-30% (P = 0.03) by the 12% treatment. We conclude from these data and others that neuronal excitability and Na(+) channel expression depend on the duration and level of CO(2) exposure and maturational changes occur in early life regarding neuronal responsiveness to CO(2).

Action Potentials↗

PubMed2006

Chronic intermittent but not constant hypoxia decreases NAA/Cr ratios in neonatal mouse hippocampus and thalamus.

Chronic constant hypoxia (CCH) and chronic intermittent hypoxia (CIH) are known to have deleterious effects on the central nervous system. Because of the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity, and this can be noninvasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either CCH, where the Fi(O(2)) was maintained at 11% continuously or to CIH, where the Fi(O(2)) was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 wk demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 wk of normoxia. Meanwhile, mice exposed to 4 wk of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases, such as obstructive sleep apnea, have the potential for inducing significant neurocognitive recovery in these patients.

Animals↗

PubMed2006

Transcriptomic changes in developing kidney exposed to chronic hypoxia.

cDNA arrays compared gene expression in kidneys of neonatal mice subjected to 1, 2, and 4 weeks of chronic constant (CCH) or intermittent (CIH) hypoxia with normoxic littermates. Five to twenty percent of genes were regulated in each condition, with greater changes in CCH. Up-regulation of 42% of the solute carriers after 1 week of CCH suggests a strong activation of pH controlling pathways. Significant reduction in expression change of genes important in growth, development, and aging as a function of time indicates reduced maturation rate in CIH and CCH treatments. Regulated genes showed gender dependence in CCH, being higher in females than males at 1 week and higher in males than females thereafter. Transcriptional control was enhanced in CCH but not in CIH. Thus, CCH and CIH both alter gene expression and retard maturation with the more profound changes occurring in CCH than in CIH.

Aging↗

PubMed2006

Effect of carbon dioxide on neonatal mouse lung: a genomic approach.

Despite the deleterious effects associated with elevated carbon dioxide (CO(2)) or hypercapnia, it has been hypothesized that CO(2) can protect the lung from injury. However, the effects of chronic hypercapnia on the neonatal lung are unknown. Hence, we investigated the effect of chronic hypercapnia on neonatal mouse lung to identify genes that could potentially contribute to hypercapnia-mediated lung protection. Newborn mouse litters were exposed to 8% CO(2), 12% CO(2), or room air for 2 wk. Lungs were excised and analyzed for morphometric alterations. The alveolar walls of CO(2)-exposed mice appeared thinner than those of controls. Analyses of gene expression differences by microarrays revealed that genes from a variety of functional categories were differentially expressed following hypercapnia treatment, including those encoding growth factors, chemokines, cytokines, and endopeptidases. In particular and of major interest, the expression level of genes encoding surfactant proteins A and D, as well as chloride channel calcium-activated 3, were significantly increased, but the expression of WNT1-inducible signaling pathway protein 2 was significantly decreased. The significant changes in gene expression occurred mostly at 8% CO(2), but only a few at 12% CO(2). Our results lead us to conclude that 1) there are a number of gene families that may contribute to hypercapnia-mediated lung protection; 2) the upregulation of surfactant proteins A and D may play a role as anti-inflammatory or antioxidant agents; and 3) the effects of CO(2) seem to depend on the level to which the lung is exposed.

Animals↗

PubMed2006

Tolerance to low O2: lessons from invertebrate genetic models.

There have been extensive studies and experiments on cells, tissues and animals that are susceptible to low O2, and many pathways have been discovered that can lead to injury in mammalian tissues. But other pathways that can help in the survival of low O2 have also been discovered in these same tissues. It should be noted, however, that the mechanisms that can lead to better survival in susceptible mammalian tissues have quantitatively a 'narrow range' for recovery, since these tissues are inherently at risk. Another strategy for understanding the susceptibility of organisms is to learn about pathways used by anoxia-resistant animals. Approximately a decade ago, I and my co-workers discovered that one such animal, Drosophila melanogaster, is very tolerant of low O2. Here, I detail some of the studies that we performed and the strategies that we developed to understand the mechanisms that underlie the fascinating resistance of Drosophila to measured partial pressure of O2 of zero. We employed three ideas to try to address our questions: (1) mutagenesis screens to identify loss-of-function mutants; (2) microarrays on adapted versus naïve flies; and (3) studying cell biology and physiology of genes that seem important in flies and mammals. The hope is to learn from these studies about the fundamental basis of tolerance to the lack of O2, and with this knowledge be able to develop better therapies for the future.

Adaptation, Physiological↗

PubMed2005

Effect of chronic continuous or intermittent hypoxia and reoxygenation on cerebral capillary density and myelination.

Chronic hypoxia, whether continuous (CCH) or intermittent (CIH), occurs in many neonatal pathological conditions, such as bronchopulmonary dysplasia and obstructive sleep apnea. In this study, we explored the effect of CCH and CIH on cerebral capillary density and myelination. We subjected CD-1 mice starting at postnatal day 2 to either CCH 11% oxygen (O(2)), or CIH 11% O(2) (4-min cycles), for periods of 2 and 4 wk followed by reoxygenation for 4 wk. Mice were deeply anesthetized and perfused. Brains were removed to fixative for 24 h, then paraffin-embedded. Coronal brain sections were taken for analysis. Immunocytochemistry for glucose transporter 1 was used to assess angiogenesis, and Luxol fast blue and fluoromyelin stains were used to assess myelination. Capillary density increased after 2-wk exposure to CIH and CCH. By 4 wk, capillary density increased in both CIH and CCH by 25% and 47%, respectively, in cortex and by 29% and 44%, respectively, in hippocampus (P < 0.05). There was a decrease in myelination in the corpus callosum of mice exposed to CIH (75% of control) and CCH (50% of control) (P < 0.05). Reoxygenation reversed the increased capillary density seen in CCH to normoxic values. However, dysmyelination that occurred in CCH-exposed mice did not show any improvement upon reoxygenation. We conclude that neonatal chronic hypoxia 1) induces brain angiogenesis, which is reversible with reoxygenation, and 2) irreversibly reduces the extent of myelination in the corpus callosum. This potential irreversible effect on myelination in early life can, therefore, have long-term and devastating effects.

Animals↗

PubMed2005

Gene expression and phenotypic characterization of mouse heart after chronic constant or intermittent hypoxia.

Chronic constant hypoxia (CCH), such as in pulmonary diseases or high altitude, and chronic intermittent hypoxia (CIH), such as in sleep apnea, can lead to major changes in the heart. Molecular mechanisms underlying these cardiac alterations are not well understood. We hypothesized that changes in gene expression could help to delineate such mechanisms. The current study used a neonatal mouse model in CCH or CIH combined with cDNA microarrays to determine changes in gene expression in the CCH or CIH mouse heart. Both CCH and CIH induced substantial alterations in gene expression. In addition, a robust right ventricular hypertrophy and cardiac enlargement was found in CCH- but not in CIH-treated mouse heart. On one hand, upregulation in RNA and protein levels of eukaryotic translation initiation factor-2alpha and -4E (eIF-2alpha and eIF-4E) was found in CCH, whereas eIF-4E was downregulated in 1- and 2-wk CIH, suggesting that eIF-4E is likely to play an important role in the cardiac hypertrophy observed in CCH-treated mice. On the other hand, the specific downregulation of heart development-related genes (e.g., notch gene homolog-1, MAD homolog-4) and the upregulation of proteolysis genes (e.g., calpain-5) in the CIH heart can explain the lack of hypertrophy in CIH. Interestingly, apoptosis was enhanced in CCH but not CIH, and this was correlated with an upregulation of proapoptotic genes and downregulation of anti-apoptotic genes in CCH. In summary, our results indicate that 1) the pattern of gene response to CCH is different from that of CIH in mouse heart, and 2) the identified expression differences in certain gene groups are helpful in dissecting mechanisms responsible for phenotypes observed.

Animals↗

PubMed2005

Intermittent hypoxia modulates Na+ channel expression in developing mouse brain.

Because our previous work showed that intermittent hypoxia alters neuronal excitability and Na+ current density, we examined in this work the effect of intermittent hypoxia on Na+ channel subtypes using 3H-saxitoxin (3H-STX) autoradiography and immunoblotting. Mice were exposed to intermittent hypoxia for 2 or 4 weeks from postnatal day 2 or 3. A 2-week intermittent hypoxia reduced cerebral STX binding density with significant decrease in Na(v)1.2 in the rostral and Na(v)1.1 in the caudal regions. In contrast, a 4-week intermittent hypoxia tended to increase STX binding density in most brain regions. Our data suggest that intermittent hypoxia differentially regulates plasma membrane Na+ channels in the developing brain, depending on duration of intermittent hypoxia.

Adaptation, Physiological↗

PubMed2005

Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development.

Lung development is a highly orchestrated process characterized by timed expression and activation of growth factor and protease/antiprotease systems. This interplay is essential in regulating vasculogenesis, alveolarization, and epithelial to mesenchymal transition during lung development. Alterations in the proteolytic/antiproteolytic balance of the lung have been associated with several respiratory diseases characterized by changes in the lung extracellular matrix (ECM). Here, we characterized the expression pattern of matrix metalloproteases (MMP) and their inhibitors, the tissue inhibitors of metalloproteases (TIMP), in human and mouse lung development. Using MMP/TIMP expression arrays, RT-PCR, Western Blotting, and ELISA analyses, we demonstrate that fetal human lung is characterized by a dominant proteolytic profile with high MMP-2 and little TIMP-3 expression. Adult human lung, in contrast, exhibits a more anti-proteolytic profile with decreased MMP-2 and increased TIMP-3 expression. MMP-14, MMP-20, TIMP-1, and TIMP-2 were constitutively expressed, irrespective of the developmental stage. Similar results were obtained using mouse lungs of different developmental stages, with the addition that in mouse lung, TIMP-2 and TIMP-3 were upregulated as lung development progressed. Exposure of neonatal mice to chronic hypoxia (10% O2), a stimulus that leads to an arrest of lung development, resulted in upregulation of MMP-2 with a concomitant downregulation of TIMP-2. These results provide a comprehensive analysis of MMP and TIMP expression during human and mouse lung development. MMP-2, TIMP-2, and TIMP-3 may be key regulatory enzymes during lung development, possibly through their complex action on ECM components, membrane receptor ectodomain shedding, and growth factor bioactivity.

Animals↗

PubMed2004

Regulatory role of dADAR in ROS metabolism in Drosophila CNS.

Pre-mRNA adenosine deaminase (ADAR) is involved in many physiological processes by either directly converting adenosine to inosine in certain pre-mRNAs or indirectly regulating expression of certain genes. Mutations of Drosophila ADAR (dADAR) results in neuronal dysfunction and hypersensitivity to oxygen deprivation. Recently, we found that the mutant flies were very resistant to paraquat, a compound that generates free radicals. In order to further characterize the neuronal role of dADAR and understand the basis for the resistance to the oxidative stress, we investigated the effect of dADAR on the expression of genes encoding scavengers of cellular reactive oxygen species (ROS) in both dADAR mutant and overexpression flies. Our data show that the expression of the genes encoding known ROS scavengers [superoxide dismutase (SOD) and catalase] is not regulated by dADAR. However, the transcripts of genes encoding two potential ROS scavengers (dhd and Cyp4g1) were robustly increased in dADAR mutant flies, and conversely both were significantly decreased in dADAR overexpressing flies. Using dhd [encoding a Drosophila homolog of the mammalian protein thioredoxin (Trx)] transgenic flies, we confirmed that the resistance of dADAR mutant flies to paraquat resulted, at least partially, from the up-regulation of dhd gene in dADAR mutant flies. Our data not only confirm the importance of ADAR in maintenance of neuronal function but also reveal its regulatory role in the expression of genes encoding ROS scavengers.

Adenosine Deaminase↗

PubMed2004

Identification of new targets of Drosophila pre-mRNA adenosine deaminase.

Adenosine deaminase acting on RNA (ADAR) in Drosophila and mammals has recently become the target of numerous investigations. It is now clear that this protein has a number of functions in the nervous system. Indeed, the mutation of ADAR in Drosophila (dADAR) results in many pathological and physiological changes, such as sensitivity to hypoxia and neuronal degeneration. To understand the full scope of dADAR function, it is crucial to identify new dADAR targets. A polyclonal antibody against inosine was developed and used to enrich inosine-containing mRNAs. The efficiency of immunoaffinity purification was confirmed for the Q/R editing site of GluR-B pre-mRNA that has been edited by ADAR2 to generate inosines at the editing site. This approach was applied to enrich inosine-containing mRNAs from total mRNAs of wild-type and dADAR mutant flies, respectively. The enriched mRNA portion was then amplified and hybridized with Drosophila cDNA arrays. With this method, over 500 mRNAs were identified as potential dADAR targets by showing a higher amount in the enriched mRNA portion from wild-type flies than from dADAR mutant flies. The occurrence of A-to-G conversion in these mRNAs was further analyzed by comparing over 7,000 Drosophila cDNAs sequences with their genomic sequences. A final list of 62 candidates was generated from the overlap of the two approaches. Twelve genes from the final list were further examined by sequencing the RT-PCR products of these genes from wild-type and dADAR mutant flies. Seven of the 12 genes were proven to have A-to-G changes in the wild-type but not in mutant flies. We conclude that the combination of immunoaffinity enrichment of inosine-containing mRNA, DNA microarrays, and sequence comparison could facilitate the discovery of new dADAR substrates, which in turn allows us to better understand the targets of dADAR and the biological function of A-to-I RNA editing in flies.

Adenosine Deaminase↗

PubMed2004

Conditional overexpression of bioactive transforming growth factor-beta1 in neonatal mouse lung: a new model for bronchopulmonary dysplasia?

Research interest in bronchopulmonary dysplasia (BPD) has steadily increased, and numerous potential mediators have been implicated in the development of the disease. Among such mediators is transforming growth factor (TGF)-beta. Unfortunately, commonly utilized murine transgenic models are not optimal to investigate the effects of TGF-beta specifically during the 2-3 wk period of alveolar formation, the developmental stage that corresponds histologically to early alveolar development in humans, and the time frame during which BPD develops. In the current study, we utilized a triple-transgenic construct to overexpress bioactive TGF-beta1 in the neonatal mouse lung during the period of alveolar formation. Lungs were then examined by histologic, Western blot, and immunofluorescent methods. We found that overexpression of bioactive TGF-beta1 in neonatal mouse lungs resulted in structural changes that have been described in BPD. Included in those characteristics are abnormal alveolar structure, cellular composition, and vascular development. Our study indicates that TGF-beta1 overexpression in the neonatal mouse lung results in histologic alterations that have striking similarities to pathologic descriptions of BPD. We encourage the use of conditional transgenic models for the study of BPD, and hypothesize that the TGF-beta system is a central mediator for the histologic alterations described in association with the disease.

Actins↗

PubMed2004

Na+/H+ exchanger 1 deficiency alters gene expression in mouse brain.

Na(+)/H(+) exchanger 1 (NHE1) is well known to function as a major regulator of intracellular pH (pH(i)). It is activated by low pH(i) and exchanges extracellular Na(+) for intracellular H(+) to maintain cellular homeostasis. Despite the fact that we now have evidence suggesting other roles for NHE1, there has been no comprehensive study investigating its role as a signaling molecule. Toward this aim, we used in this study NHE1 null mutant mice and cDNA microarrays to investigate the effects of NHE1 on global gene expression in various regions of the brain, e.g., cortex, hippocampus, brain stem-diencephalon, and cerebellum. We found that a total of 35 to 79 genes were up- or downregulated in each brain region, with the majority being downregulated. The effect of NHE1 null mutation on gene expression is region specific, and only 11 genes were changed in all brain regions studied. Further analysis of the cis-regulatory regions of downregulated genes revealed that transcription suppressors, BCL6 and E4BP4, were probable candidates that mediated the inhibitory effect of NHE1 null mutation. One of the genes, MCT-13, was not only downregulated in the NHE1 null mutant brain but also in tissue cultures treated with an NHE1 inhibitor. We conclude that 1) a relatively small number of genes were altered in the NHE1 null mouse brain; 2) the effects of NHE1 null mutation on gene expression are region specific; and 3) several genes implicated in neurodegeneration have altered expression, potentially offering a molecular explanation for the phenotype of the NHE1 null mouse.

Acidosis↗

PubMed2004

Effect of chronically elevated CO2 on CA1 neuronal excitability.

To study the effect of chronically elevated CO(2) on the excitability and function of neurons, we exposed mice to 7.5-8% CO(2) for approximately 2 wk (starting at 2 days of age) and examined the properties of freshly dissociated hippocampal neurons. Neurons from control mice (CON) and from mice exposed to chronically elevated CO(2) had similar resting membrane potentials and input resistances. CO(2)-exposed neurons, however, had a lower rheobase and a higher Na(+) current density (580 +/- 73 pA/pF; n = 27 neurons studied) than did CON neurons (280 +/- 51 pA/pF, n = 34; P < 0.01). In addition, the conductance-voltage curve was shifted in a more negative direction in CO(2)-exposed than in CON neurons (midpoint of the curve was -46 +/- 3 mV for CO(2) exposed and -34 +/- 3 mV for CON, P < 0.01), while the steady-state inactivation curve was shifted in a more positive direction in CO(2)-exposed than in CON neurons (midpoint of the curve was -59 +/- 2 mV for CO(2) exposed and -68 +/- 3 mV for CON, P < 0.01). The time constant for deactivation at -100 mV was much smaller in CO(2)-exposed than in CON neurons (0.8 +/- 0.1 ms for CO(2) exposed and 1.9 +/- 0.3 ms for CON, P < 0.01). Immunoblotting for Na(+) channel proteins (subtypes I, II, and III) was performed on the hippocampus. Our data indicate that Na(+) channel subtype I, rather than subtype II or III, was significantly increased (43%, n = 4; P < 0.05) in the hippocampi of CO(2)-exposed mice. We conclude that in mice exposed to elevated CO(2), 1) increased neuronal excitability is due to alterations in Na(+) current and Na(+) channel characteristics, and 2) the upregulation of Na(+) channel subtype I contributes, at least in part, to the increase in Na(+) current density.

Action Potentials↗

PubMed2004

Role of trehalose phosphate synthase and trehalose during hypoxia: from flies to mammals.

Trehalose is a nonreducing disaccharide in which the two glucose units are linked in an alpha,alpha-1,1-glycosidic linkage. The best known and most widely distributed pathway of trehalose synthesis involves the transfer of glucose from UDP-glucose to glucose 6-phosphate to form trehalose-6-phosphate and UDP via the trehalose-6-phosphate synthase (TPS1). Trehalose-6-phosphate phosphatase (TPS2) then converts trehalose-6-phosphate to free trehalose. This sugar is present in a wide variety of organisms, including bacteria, yeast, fungi, insects, invertebrates and plants, and because of its particular physical features, trehalose is able to protect the integrity of cells against a variety of environmental stresses such as desiccation, dehydration, heat, cold and oxidation. Our current studies described here indicate that trehalose protects Drosophila and mammalian cells from hypoxic and anoxic injury. The mechanism of this protection is probably related to a decrease in protein denaturation through protein-trehalose interactions.

Animals↗

PubMed2003

A critical role of neural-specific JNK3 for ischemic apoptosis.

c-Jun N-terminal kinase (JNK) signaling is an important contributor to stress-induced apoptosis, but it is unclear whether JNK and its isoforms (JNK1, JNK2, and JNK3) have distinct roles in cerebral ischemia. Here we show that JNK1 is the major isoform responsible for the high level of basal JNK activity in the brain. In contrast, targeted deletion of Jnk3 not only reduces the stress-induced JNK activity, but also protects mice from brain injury after cerebral ischemia-hypoxia. The downstream mechanism of JNK3-mediated apoptosis may include the induction of Bim and Fas and the mitochondrial release of cytochrome c. These results suggest that JNK3 is a potential target for neuroprotection therapies in stroke.

Animals↗