Sustained Elevation of Intracellular cGMP Causes Oxidative Stress Triggering Calpain-Mediated Apoptosis in Photoreceptor Degeneration

Sharma, Ashish K.; Rohrer, Bärbel

doi:10.1080/02713680601161238

Cited by 62 publications

(49 citation statements)

References 34 publications

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“…PKG I expression was not determined in the studies demonstrating a lack of cGMP-mediated protection (8,54,60). A recent study in retinal cells (52) found that cGMP triggered apoptosis through the direct activation of a cyclic nucleotide-gated cation channel thus demonstrating a PKG I -independent, proapoptotic cGMP effect. In contrast, our results in PKG I Ϫ/Ϫ MLMVECs (Fig.…”

Section: Discussionmentioning

confidence: 95%

cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism

Stephens

Rentsendorj

Servinsky

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Stephens RS, Rentsendorj O, Servinsky LE, Moldobaeva A, Damico R, Pearse DB. cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism. Am J Physiol Lung Cell Mol Physiol 299: L323-L333, 2010. First published May 7, 2010 doi:10.1152/ajplung.00442.2009.-Increasing evidence suggests that endothelial cytotoxicity from reactive oxygen species (ROS) contributes to the pathogenesis of acute lung injury. Treatments designed to increase intracellular cGMP attenuate ROSmediated apoptosis and necrosis in several cell types, but the mechanisms are not understood, and the effect of cGMP on pulmonary endothelial cell death remains controversial. In the current study, increasing intracellular cGMP by either 8pCPT-cGMP (50 M) or atrial natriuretic peptide (10 nM) significantly attenuated cell death in H2O2-challenged mouse lung microvascular (MLMVEC) monolayers. 8pCPT-cGMP also decreased perfusate LDH release in isolated mouse lungs exposed to H 2O2 or ischemia-reperfusion. The protective effect of increasing cGMP in MLMVECs was accompanied by enhanced endothelial H 2O2 scavenging (measured by H2O2 electrode) and decreased intracellular ROS concentration (measured by 2=,7=-dichlorofluorescin fluorescence) as well as decreased phosphorylation of p38 MAPK and Akt. The cGMP-mediated cytoprotection and increased H2O2 scavenging required Ͼ2 h of 8pCPT-cGMP incubation in wild-type MLMVEC and were absent in MLMVEC from protein kinase G (PKG I)Ϫ/Ϫ mice suggesting a PKGI-mediated effect on gene regulation. Catalase and glutathione peroxidase 1 (Gpx-1) protein were increased by cGMP in wild-type but not PKG IϪ/Ϫ MLMVEC monolayers. Both the cGMP-mediated increases in antioxidant proteins and H 2O2 scavenging were prevented by inhibition of translation with cycloheximide. 8pCPT-cGMP had minimal effects on catalase and Gpx-1 mRNA. We conclude that cGMP, through PKGI, attenuated H 2O2-induced cytotoxicity in MLMVEC by increasing catalase and Gpx-1 expression through an unknown posttranscriptional effect. apoptosis; necrosis; hydrogen peroxide; catalase; glutathione peroxidase INCREASED ENDOTHELIAL CELL DEATH from reactive oxygen species (ROS) contributes to the pathogenesis of acute lung injury (ALI) (56). Based on this concept, inhibition of apoptosis has been proposed as a potential ALI therapy (32). Unfortunately, the complex spectrum of cell death from the carefully orchestrated process of apoptosis to necrosis can result in unpredictable effects when specific cell death pathways are blocked (56). The pharmacological inhibition of ROS production (18) or the administration of endothelial-targeted antioxidant enzymes (53) may prove to be safer approaches to this problem, but these strategies have not yet translated into clinical therapies.In some clinical situations, an oxidant endothelial insult can be predicted in advance, allowing the potential for a preconditioning treatment to bolster endogenous antioxidant pathways (36). For example,...

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Section: Discussionmentioning

confidence: 95%

cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism

Stephens

Rentsendorj

Servinsky

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…ROS can lead to calpain activation (47,48), although this pathway has not been implicated previously in inflammation. We used ALLN, a calpain inhibitor, to test whether calpain is in- fl/fl LysM-Cre − BMM and Atg5 fl/fl LysM-Cre + BMM knocked down with siRNA for Calpain S1.…”

Section: (B-d) Intracellular Levels Of Il-17a (B and C) And Ifn-γ (D mentioning

confidence: 97%

Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation

Castillo¹,

Dekonenko²,

Arko‐Mensah³

et al. 2012

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

388

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Autophagy is a cell biological pathway affecting immune responses. In vitro, autophagy acts as a cell-autonomous defense against Mycobacterium tuberculosis, but its role in vivo is unknown. Here we show that autophagy plays a dual role against tuberculosis: antibacterial and anti-inflammatory. M. tuberculosis infection of Atg5 fl/fl LysM-Cre + mice relative to autophagy-proficient littermates resulted in increased bacillary burden and excessive pulmonary inflammation characterized by neutrophil infiltration and IL-17 response with increased IL-1α levels. Macrophages from uninfected Atg5 fl/fl LysM-Cre + mice displayed a cell-autonomous IL-1α hypersecretion phenotype, whereas T cells showed propensity toward IL-17 polarization during nonspecific activation or upon restimulation with mycobacterial antigens. Thus, autophagy acts in vivo by suppressing both M. tuberculosis growth and damaging inflammation.utophagy is a fundamental cell biological process (1) with impact on aging, development, cancer, neurodegeneration, myodegeneration, metabolic disorders (2), idiopathic inflammatory diseases, and infection and immunity (3). Much of the physiological effects of autophagy are the result of degradative activities of autophagy (1), although biogenesis and secretory roles (4-6) of autophagy are beginning to be recognized (7). The execution of autophagy depends on factors collectively termed "Atg proteins," such as Atg5 (1) and Beclin 1 (Atg6) (8), whereas regulation of autophagy responds to various inputs via mammalian target of rapamycin (mTOR), including the presence of microbes (9), the TAB2/3-TAK1-IKK signaling axis (10), and processes downstream of pattern-recognition receptors and immune cytokine activation (3,(11)(12)(13).In the context of its immunological functions, autophagy acts in four principal ways (14). (i) Autophagy cooperates with conventional pattern-recognition receptors (PRRs), such as Toll-like receptors, RIG-I-like receptors (RLRs), and NOD-like receptors, and acts as both a regulator (11,12,15,16) and an effector of PRR signaling (17-19). (ii) Autophagy affects the presentation of cytosolic antigens in the context of MHC II molecules (20) in T-cell development, differentiation, polarization, and homeostasis (21,22). (iii) Most recently, autophagy has been shown to contribute to both the negative (6,7,(23)(24)(25) and positive (6, 7) regulation of unconventional secretion of the leaderless cytosolic proteins known as "alarmins," such as IL-1β and HMGB1. (iv) Autophagy can capture and eliminate intracellular microbes, including Mycobacterium tuberculosis (17, 26-29), which was one of the first two bacterial species (26, 30) to be recognized as targets for autophagic removal. This activity recently has been shown to depend on the recognition and capture of microbes by adaptors that represent a specialized subset of PRRs termed "sequestosome-like receptors" (SLRs) (31).M. tuberculosis is one of the first microbes recognized as being subject to elimination by immunological autophagy by murine and human...

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“…The fundamental outcome from our studies is that even a retina that is metabolically overloaded can maintain its function until a threshold level for cell death is reached. When we applied sildenafil to the P23H-3 rat model, we were able to modify retinal LDH activity, which suggests a downregulation of aerobic metabolism and/or accelerated photoreceptor death, reminiscent of that noted in other retinal dystrophy models (RCS and rd/rd retina) (3,9,87). Inhibition of phosphodiesterase affects the already compromised cellular environment of the P23H-3 retina (high oxygen tension and high ATP levels) but not that of the normal SD retina.…”

Section: C771mentioning

confidence: 62%

Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa

Acosta¹,

Shin²,

Ready³

et al. 2010

American Journal of Physiology-Cell Physiology

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-We determined the metabolic changes that precede cell death in the dystrophic proline-23-histidine (P23H) line 3 (P23H-3) rat retina compared with the normal SpragueDawley (SD) rat retina. Metabolite levels and metabolic enzymes were analyzed early in development and during the early stages of degeneration in the P23H-3 retina. Control and degenerating retinas showed an age-dependent change in metabolite levels and enzymatic activity, particularly around the time when phototransduction was activated. However, lactate dehydrogenase (LDH) activity was significantly higher in P23H-3 than SD retina before the onset of photoreceptor death. The creatine/phosphocreatine system did not contribute to the increase in ATP, because phosphocreatine levels, creatine kinase, and expression of the creatine transporter remained constant. However, Na ϩ -K ϩ -ATPase and Mg 2ϩ -Ca 2ϩ -ATPase activities were increased in the developing P23H-3 retina. Therefore, photoreceptor apoptosis in the P23H-3 retina occurs in an environment of increased LDH, ATPase activity, and higher-than-normal ATP levels. We tested the effect of metabolic challenge to the retina by inhibiting monocarboxylate transport with ␣-cyano-4-hydroxycinnamic acid or systemically administering the phosphodiesterase inhibitor sildenafil. Secondary to monocarboxylate transport inhibition, the P23H-3 retina did not demonstrate alterations in metabolic activity. However, administration of sildenafil significantly reduced LDH activity in the P23H-3 retina and increased the number of terminal deoxynucleotidyl transferase biotin-dUPT nick end-labeled photoreceptor cells. Photoreceptor cells with a rhodopsin mutation display an increase in apoptotic markers secondary to inhibition of a phototransduction enzyme (phosphodiesterase), suggesting increased susceptibility to altered cation entry.phosphocreatine; ATP; ␣-cyano-4-hydroxycinnamic acid; sildenafil; lactate dehydrogenase; ATPase RETINITIS PIGMENTOSA is the term given to a family of retinal disorders that cause blindness due to gradual loss of photoreceptors. Although photoreceptor cell death in retinitis pigmentosa has a number of underlying causes that include rhodopsin mutations (94), altered photoreceptor oxygen environment (36,103,104), disk morphogenesis, retinal pigment epithelium dysfunction, and chronic activation of photoreceptor transduction cascade (80), the understanding of the cell death pathways is still evolving. It is generally accepted that cell death in inherited forms of retinal degeneration occurs via the process of apoptosis (16,66,82,92), an active cellular process requiring energy (25). The concept of apoptosis as the major pathway of cell death in inherited forms of retinal degeneration has recently been questioned with a proposal that nonapoptotic pathways also contribute to photoreceptor death (7,23,42,63,86,107).Increased metabolic activity is a potential cause of photoreceptor death in some models of retinal dystrophy, such as the rd/rd (rd1) model, where cyclic nucleotide channels are malfu...

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Sustained Elevation of Intracellular cGMP Causes Oxidative Stress Triggering Calpain-Mediated Apoptosis in Photoreceptor Degeneration

Cited by 62 publications

References 34 publications

cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism

cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism

Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation

Retinal metabolic state of the proline-23-histidine rat model of retinitis pigmentosa

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