Reduction of Apurinic/Apyrimidinic Endonuclease Expression After Transient Global Cerebral Ischemia in Rats

Kawase, Makoto; Fujimura, Miki; Morita-Fujimura, Yuiko; Chan, Pak H.

doi:10.1161/01.str.30.2.441

Cited by 80 publications

(54 citation statements)

References 57 publications

(49 reference statements)

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“…Global ischemia reduced APE1 mRNA and protein expression and DNA repair activity in neurons destined to die, evident 3 to 24 h after reperfusion (Fig. S1); the decrease in APE1 protein is in corroboration of others (10). In contrast, APE1 mRNA and protein expression and AP site-specific endonuclease activity were up-regulated in the resistant CA3 and DG (Fig.…”

Section: Resultssupporting

confidence: 72%

“…Long understood to lead to genetic mutations associated with spontaneous tumor formation, AP sites have also been found to induce cell death in yeast (5), and deficiency in APE1 expression and activity exacerbates oxidative injury in multiple models, including neurons (12,20,21). Unrepaired AP sites accumulate following cerebral ischemia (4,6), and sustained decrease in APE1 protein expression has been observed to precede cell death in injured cell populations (10,22,23) (Fig. 2A and Fig.…”

Section: Discussionmentioning

confidence: 94%

“…Following cerebral ischemia, APE1 expression and activity are closely correlated with cellular survival comparing different brain regions and in response to different experimental interventions. APE1 expression and BER activity are significantly depressed before the onset of cell death in regions severely damaged by cerebral ischemia (6,10). In contrast, APE1 activity is enhanced by sublethal insults (6).…”

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confidence: 99%

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Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia

Stetler

Gao

Zukin

et al. 2010

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

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Inducible DNA repair via the base-excision repair pathway is an important prosurvival mechanism activated in response to oxidative DNA damage. Elevated levels of the essential base-excision repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 correlate closely with neuronal survival against ischemic insults, depending on the CNS region, protective treatments, and degree of insult. However, the precise mechanisms by which this multifunctional protein affords protection and is activated by upstream signaling pathways in postischemic neurons are not well delineated. Here we show that intracerebral administration of pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenously occurring small neuropeptide, induces expression of APE1 in hippocampal neurons. Induction of APE1 expression requires PKAand p38-dependent phosphorylation of cAMP response-element binding and activating transcription factor 2, which leads to transactivation of the APE1 promoter. We further show that PACAP markedly reduces oxidative DNA stress and hippocampal CA1 neuronal death following transient global ischemia. These effects occurred,atleastinpart,viaenhancedAPE1expression.Furthermore, the DNA repair function of APE1 was required for PACAP-mediated neuroprotection. Thus, induction of DNA repair enzymes may be a uniquestrategy forneuroprotectionagainsthippocampalinjury.activating transcription factor 2 | cAMP response-element binding | delayed neurodegeneration | DNA repair | oxidative stress O xidative stress is a hallmark of neurological disorders, including cerebral ischemia. Ischemic injury rapidly elicits oxidative DNA damage either directly via reactive oxygen species attack or indirectly via oxidization of lipids or proteins (1-3). These actions induce DNA lesions, involving base modifications and damage to the sugar moiety in the DNA, formation of abasic (apurinic/apyrimidinic, AP) sites, single strand breaks, and DNA intra-or interstrand crosslinks. Of these lesions, AP sites and single strand breaks are highly prevalent types of DNA damage in insulted neurons (4). Whereas the accumulation of unrepaired DNA ultimately induces cell death, active repair of DNA promotes cell survival (4-6).In neurons, base-excision repair (BER) is the predominant mechanism for repair of oxidative DNA lesions (7). BER is a three-step process. First, 5′-acting AP endonuclease 1 (APE1, also known as redox-effector factor 1) cleaves the phosphodiester backbone, then β-polymerase or alternative repair proteins, such as FEN1 or PCNA, fill in the gap with newly synthesized nucleotides, and finally a DNA ligase seals the nick. In several models of ischemia, oxidative DNA damage is reversible in regions that survive (4,6,8), raising the possibility that repair of DNA damage via BER is required for cell survival following ischemia.APE1 is an attractive target for neuroprotection, as it is a critical component of the BER process (9) and as also has redox and transcription-regulation activities. Following cerebral ischemi...

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Section: Resultssupporting

confidence: 72%

Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

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Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia

Stetler

Gao

Zukin

et al. 2010

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

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“…[1][2][3] The accumulation of damaged DNA lesions results in cell death, due to various induced intracellular signaling pathways. [4][5][6] In addition, brain ischemia induces specific expression of genes related to the DNA repair pathway. Proliferating cell nuclear antigen (PCNA), which is required for DNA synthesis and nucleotide excision repair (NER), is upregulated in the CA3/dentate gyrus and downregulated in the vulnerable CA1 region following global ischemia.…”

Section: Introductionmentioning

confidence: 99%

Excision repair cross-complementing 1 expression protects against ischemic injury following middle cerebral artery occlusion in the rat brain

Yang

Shen

et al. 2009

Gene Ther

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To study the effects of excision repair cross-complementing 1 (ERCC1) on the pathophysiological process of brain ischemia, we examined the changes in ERCC1 expression, as well as the functional significance of ERCC1 in the rat brain following middle cerebral artery occlusion (MCAO). The results were as follows: (1) ERCC1 immunopositive cells were widely distributed in various brain regions. ERCC1 expression was localized to the nuclei of neurons and astrocytes. (2) ERCC1 expression, as determined by western blot, increased at 3 days, remaining until 14 days, in the ipsilateral cortex and striatum following MCAO. Immunohistochemical analysis demonstrated that ischemia induced increased ERCC1 expression within the periinfarct core, with increasingly less expression toward the core. (3) Knockdown of ERCC1 expression by intraventricular injection of antisense plasmids increased DNA damage and infarct volume in the ischemic brain. (4) ERCC1 overproduction, by injection of expression plasmids, significantly reduced infarct volume and the accumulation of DNA-damaged neurons. Taken together, these results indicate that both endogenous ERCC1 and exogenous ERCC1 have an important neuroprotective function in the brain. In addition, administration of ERCC1 to the brain could prove to be a successful strategy for neuronal protection against ischemic injury.

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“…We and others have demonstrated that enhanced APE1 activity by means of transgenic overexpression or APE1 expression-inducing peptides, such as the pituitary adenylate cyclase-activating polypeptide (PACAP), confers robust neuroprotection against ischemic brain injury (10-12). Furthermore, a strong correlation exists between loss of APE1 expression in ischemic neurons and neuronal cell death after ischemia (9,(13)(14)(15). Energy failure after ischemia has been speculated to deplete APE1 expression, thereby triggering neuronal death (16).…”

mentioning

confidence: 99%

APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury

Stetler

Gao

Leak

et al. 2016

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

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A major hallmark of oxidative DNA damage after stroke is the induction of apurinic/apyrimidinic (AP) sites and strand breaks. To mitigate cell loss after oxidative DNA damage, ischemic cells rapidly engage the base excision-repair proteins, such as the AP site-repairing enzyme AP endonuclease-1 (APE1), also named redox effector factor-1 (Ref-1). Although forced overexpression of APE1 is known to protect against oxidative stress-induced neurodegeneration, there is no concrete evidence demonstrating a role for endogenous APE1 in the long-term recovery of gray and white matter following ischemic injury. To address this gap, we generated, to our knowledge, the first APE1 conditional knockout (cKO) mouse line under control of tamoxifendependent Cre recombinase. Using a well-established model of transient focal cerebral ischemia (tFCI), we show that induced deletion of APE1 dramatically enlarged infarct volume and impaired the recovery of sensorimotor and cognitive deficits. APE1 cKO markedly increased postischemic neuronal and oligodendrocyte degeneration, demonstrating that endogenous APE1 preserves both gray and white matter after tFCI. Because white matter repair is instrumental in behavioral recovery after stroke, we also examined the impact of APE1 cKO on demyelination and axonal conduction and discovered that APE1 cKO aggravated myelin loss and impaired neuronal communication following tFCI. Furthermore, APE1 cKO increased AP sites and activated the prodeath signaling proteins, PUMA and PARP1, after tFCI in topographically distinct manners. Our findings provide evidence that endogenous APE1 protects against ischemic infarction in both gray and white matter and facilitates the functional recovery of the central nervous system after mild stroke injury.ischemia | neurodegeneration | base excision repair | oxidative DNA damage | white matter injury F ocal ischemic injury in the brain is both a spatial and temporal event, wherein the infarct zone expands gradually over several days (1, 2). However, if the stroke insult is moderate, the periinfarct regions may recover over time. The spontaneous recovery of periinfarct structures and neurological functions creates an opportunity to research the molecular mechanisms underlying endogenous neuroprotection and neural repair, which may accelerate the discovery of rational therapeutic targets for stroke treatment.Oxidative DNA damage (ODD) is an early event following cerebral ischemia and reperfusion (3, 4), and reversal of ODD in penumbral regions is associated with eventual recovery from such insult (4, 5). Repair of ODD by the base excision-repair (BER) pathway targets oxidized DNA base lesions through a multistep process. First, base lesions are recognized by DNA glycosylases, which cleave the damaged bases and form temporary apurinic/ apyrimidinic (AP) sites. The AP sites are then recognized by the critical BER enzyme, AP endonuclease-1/redox effector factor-1 (referred to here as APE1) (6, 7). APE1 repairs AP sites by cleaving the phosphodiester backbone 5′ to the AP ...

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Reduction of Apurinic/Apyrimidinic Endonuclease Expression After Transient Global Cerebral Ischemia in Rats

Cited by 80 publications

References 57 publications

Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia

Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia

Excision repair cross-complementing 1 expression protects against ischemic injury following middle cerebral artery occlusion in the rat brain

APE1/Ref-1 facilitates recovery of gray and white matter and neurological function after mild stroke injury

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