© 1999 American Heart Association, Inc.
Mini Review |
Nitric Oxide as a Bifunctional Regulator of Apoptosis
From the Department of Surgery (Y.-M.K., C.A.B., T.R.B.), University of Pittsburgh, Pittsburgh, Pa; Department of Molecular and Cellular Biology (Y.-M.K.), College of Medicine, Kangwon National University, Chunchon, Kanwon-do, Korea.
Correspondence to Timothy R. Billiar, MD, Watson Professor of Surgery, University of Pittsburgh Medical Center, A1010-Presbyterian University Hospital, Pittsburgh, PA 15213.
Key Words: nitric oxide • apoptosis • caspase • cGMP • peroxynitrite
It was inevitable that important relationships between two of the most intensely studied topics in biomedical research, apoptosis and nitric oxide (NO), would become apparent. Apoptosis is essential to normal development as well as physiological cell turnover. Although apoptosis in excess can manifest as tissue damage, a failure to undergo apoptosis constitutes pathological cellular overgrowth. It is now evident that NO and its reaction products can either promote or prevent apoptosis in a multitude of settings. The ubiquitous distribution of the NO synthases and the remarkable diffusibility and diverse chemical reactivity of NO in biological systems make this molecule unique among the regulators of apoptosis. Understanding the factors that govern the consequences of NO exposure on cell viability and identifying the conditions in which NO regulation of apoptosis contribute to pathology are topics of considerable interest and potential importance. In this article, we will review the recent observations on NO as a regulator of apoptosis.
Apoptosis, or programmed cell death, is distinguished from lytic or necrotic cell death by specific biochemical and structural events (see recent review in Reference 11 ). Apoptogenic signals trigger cell-specific signaling pathways, including protease activation, followed by the appearance of morphological changes characteristic of cells undergoing apoptosis, including condensation of nuclei and cytoplasm, blebbing of the cytoplasmic membranes, and finally fragmentation into apoptotic bodies that are phagocytosed by neighboring cells. The elucidation of the signaling events in apoptosis is occurring at a rapid pace and includes the identification of the key roles of cysteine proteases (known as caspases), Bcl-2 family members, and mitochondria.
Caspases, the mammalian counterpart of ced-3 in Caenorhabditis elegans, are a family of cysteine proteases now known to contain at least 14 homologs. Ectopic expression of any of the caspase family proteases can cause apoptosis; however, not all caspase family proteases have been definitively linked to apoptosis. Caspase family genes encode proenzyme forms that require proteolytic cleavage for activation. Caspases can propagate apoptotic signaling by cleaving/activating other caspases, or they can execute the terminal events in apoptosis by cleaving key death substrates. For example, caspase-9 cleaves/activates caspase-3, whereas caspase-3 cleaves specific target proteins, including poly(ADP-ribose) polymerase (PARP), DNA-dependent kinase, and the inhibitor of the caspase-dependent activated deoxyribonuclease (ICAD). The antiapoptotic effect of compounds that inhibit either the activation or activity of caspase-3–like proteases suggests that apoptosis can be regulated by modification of the protease-signaling cascade. One mechanism by which Bcl-2, itself a substrate for caspase-3, prevents cell death during physiological and pathophysiological processes is through the inhibition of mitochondrial cytochrome C release. The release of cytochrome C results in the activation of caspase-9. Although endogenous inhibitors of caspase activation and activity have been described, none has been shown to be more prevalent than NO.
NO is short-lived and is synthesized from L-arginine by the catalytic reaction of NO synthases (NOSs) (reviewed in Reference 22 ). NOSs are expressed in microorganisms, plants, and mammals, in addition to participating in diverse physiological functions including neurotransmission, regulation of vascular tone, cellular communication, inflammation, and immune responses. The mammalian NOS isoforms include the neuronal type 1 isoform (nNOS), the inducible form type 2 (iNOS), and the endothelial type 3 (eNOS). nNOS and eNOS are constitutively expressed enzymes and are regulated predominantly at the posttranslational level. iNOS is constitutively expressed in only a few cell types but can be induced in essentially every cell when appropriately stimulated. Rate of transcription is one important level of regulation for iNOS. The comparatively small amount of NO produced by constitutive NOS in endothelial and neuronal cells is important for cellular signaling events such as blood pressure regulation and neurotransmission. The much larger amount of NO generated by iNOS functions as both a regulator and effector during infection and inflammation. One effector function includes direct cytotoxicity toward tumor cells, microorganisms, and host cells. The cytotoxic capacity of NO has been confirmed in numerous systems using diverse cell targets. In many circumstances, the cytotoxicity is the result of the interaction of NO with superoxide to form peroxynitrite, a potent oxidant. The cytotoxicity of NO produced by iNOS as well as by nNOS has been the topic of intense study for more than a decade; however, more recently, the potent antiapoptotic activity of NO has also received a great deal of attention.
Proapoptotic Effect of NO
The importance of NO-mediated cytotoxicity has been appreciated
since the L-arginine
NOX pathway
was first identified in macrophages.3 The capacity
of NO to induce apoptosis was first appreciated by Albina et
al,4 who showed that NO caused apoptosis in
macrophages. Since then, several cell types have been shown to
undergo apoptosis in response to NO or peroxynitrite. Primary
cell types that are particularly sensitive include
macrophages,4 pancreatic islets,5
thymocytes,6 and certain neurons.7 The
proapoptotic effect on these cells seems to be independent of
cGMP accumulation; however, NO has been shown to induce
apoptosis via the stimulation of soluble guanylyl cyclase in
vascular smooth muscle cells in vitro.8 Although the
factors that determine cell-specific sensitivity to NO-mediated
apoptosis are not clearly elucidated, the induction of
apoptosis by NO can be the result of DNA damage. DNA damage
results in the accumulation of the tumor suppressor protein p53, which
has been described as an essential and early indicator of NO-induced
apoptosis.9 p53, in turn, induces cell cycle
arrest by upregulating p21 or apoptosis. The induction of
apoptosis often requires exposure to high levels of exogenous
NO donors. Short-term exposure to high levels of NO may overwhelm
natural protective pathways, leading to the activation of
apoptotic signaling pathways. Such toxic levels of NO may have
limited relevance to the in vivo situation. Another important factor in
the susceptibility to NO is whether a cell type has the capacity to use
NO for protection. For example, some cells are protected by cGMP;
therefore, cells that possess this signaling pathway may be protected
by NO.
NO can interact with superoxide anion to produce the potent oxidant peroxynitrite. Some studies suggest that the proapoptotic effect of NO is a result of the formation of peroxynitrite, inducing apoptotic DNA fragmentation and p53-dependent apoptosis.2 9 The formation of peroxynitrite is determined by the ratio of NO to superoxide, and the cellular susceptibility to peroxynitrite is dependent in large part on the levels of antioxidants (eg, thiols).
Antiapoptotic Actions of NO
In view of the extensive literature describing NO as a cytotoxic effector, it is not surprising that NO, especially iNOS-generated NO, was rapidly accepted as a potent inducer of apoptosis. A seminal paper by Mannick et al10 in 1994, however, forced a paradigm shift. These authors showed that endogenous iNOS expression or exposure to low doses of NO donors inhibited apoptosis in human B lymphocytes. Following this report, similar findings were described in several in vitro cell culture systems including splenocytes,11 eosinophils,12 13 endothelial cells,14 hepatocytes,15 16 17 and cell lines.18 In addition, animal experiments demonstrated that lipopolysaccharide (LPS)-induced hepatic apoptosis was increased by administration of NOS inhibitors,19 and administration of a liver-specific NO donor almost completely blocked the massive hepatic apoptosis induced by tumor necrosis factor (TNF) plus D-galactosamine administration.16 Several general aspects of NO-mediated inhibition of apoptosis warrant comment. First, NO has been shown to inhibit apoptosis both in vitro and in vivo in certain cell types.16 17 Second, NO inhibits apoptosis induced by many different stimuli, including growth factor withdrawal, TNF, or Fas.17 Third, multiple mechanisms for the inhibition of apoptosis by NO may exist in a single cell type. For example, NO blocks apoptosis in hepatocytes both via cGMP-mediated interruption of apoptotic signaling and direct inhibition of caspase activity.17 Finally, the levels of NO generated by either constitutive or iNOS can inhibit apoptosis. In fact, in endothelial cells, constitutive eNOS was adequate to inhibit TNF-induced apoptosis14 while overexpression of iNOS also effectively suppressed LPS-induced apoptosis without toxicity.20
Antiapoptotic Mechanisms
The reactivity of NO in biological systems is complex and permits NO to exert a wide range of actions. Studies on the antiapoptotic mechanisms of NO have identified a series of NO target interactions that range from indirect and nonspecific to direct interaction with apoptotic machinery.
Induction of Cytoprotective Stress Proteins
NO can oxidize intracellular reduced glutathione and thereby
change the antioxidant levels within the cell, resulting in oxidative
or nitrosative stress. This action stimulates the induction of heat
shock proteins HSP32 (heme oxygenase) and HSP70, which
protect cells from apoptotic cell death induced by TNF plus
actinomycin D15 and oxidative or nitrosative
stress.21 The molecular mechanism underlying
antiapoptotic effect by NO-mediated HSP expression may be
associated with two possibilities.22 The first is the
direct suppression of apoptotic signal transduction involving
the inhibition of caspase family protease activation. The second
involves the chaperon-mediated import of precursor proteins into
mitochondria by HSPs. This action controls mitochondrial function and
membrane permeability thereby preventing the release of cytochrome C
that is required for further activation of caspases.
cGMP-Dependent Inhibition of Apoptotic Signal
Transduction
One of the first molecular targets to be identified for NO was the
heme protein soluble guanylyl cyclase. NO activates guanylyl
cyclase by interacting with its heme and generates cGMP from GTP.
Intracellular elevation of cGMP decreases cellular
Ca2+ concentration, which is one of the key
signals of apoptosis. In some cell types shown to be protected
by NO (including hepatocytes, neuronal PC12 cells, and
splenocytes), cGMP prevents apoptotic cell
death.11 17 The molecular mechanisms underlying the
NO/cGMP inhibition of apoptosis could involve the activation of
cGMP-dependent protein kinase and the inhibition of caspase
activation.17 The inhibition of caspase activation may
then limit Bcl-2 degradation and thus explain the increase in Bcl-2
levels observed in splenocytes exposed to NO or cGMP11
(Figure
). However, the mechanism by which
cGMP or G kinase suppresses apoptotic signaling remains
unknown.
|
Suppression of Caspase Activity
All caspase proteases contain a single cysteine at the enzyme
catalytic site that is essential for activity.14 For
caspase-3, the essential cysteine is cys163. This thiol is susceptible
to redox modification and can be efficiently S-nitrosylated
in the presence of NO.14 17 23 24 Suppression of
caspase activity by NO has been demonstrated using several purified
human caspases23 and has been shown to account, at least
in part, for the suppression of apoptosis by NO in
endothelial cells,20
hepatocytes,17 and several tumor cell
lines.24 Evidence for S-nitrosylation of
caspase-3 and caspase-1 in vivo has been
demonstrated.17 25 S-nitrosylation
requires the formation of an NO reaction product with chemical
reactivity of NO+, necessitating that NO first
give up an electron. Common intracellular electron acceptors include
O2 and Fe3+. Therefore, the
capacity of NO to S-nitrosylate caspases will depend on the
abundance of these molecules and the availability of other thiol
targets such as glutathione. In support of this prediction, we
have found that S-nitrosylation of caspases occurs extremely
efficiently in hepatocytes but not in MCF adenocarcinoma
cells, unless the MCF cells are preloaded with
iron.26 An important feature of NO inhibition of
caspase activity is that NO can rescue a cell from apoptosis
even after the caspase cascade has been activated. Because NO
easily diffuses within a cell, as well as from cell to cell, NO can
efficiently guard against aberrant activation of caspases.
Inhibition of Cytochrome C Release
Recent studies have shown that cytochrome C release from
mitochondria is a key component in the activation of
caspases.1 Although it is known that Bcl-2 can inhibit
cytochrome C release, we have observed that cytochrome C release can
also be inhibited by the NO pathway.26 Furthermore, Bcl-2
cleavage can be inhibited by the caspase-3–like inhibitor
Ac-DEVD-cho and/or NO, suggesting that activated
caspase-3–like proteases are responsible for Bcl-2 protein cleavage
and the inactivation of the antiapoptotic function of
Bcl-2.26 By interrupting this step, NO appears to suppress
cytochrome C release, which is a key factor for the amplification of
apoptotic signaling through caspase-9 (Figure
).
Conclusion
The decision for a cell to undergo apoptosis is the result
of a shift in the balance between the antiapoptotic and
proapoptotic forces within a cell. The accumulated data
indicate that physiologically relevant levels
of NO contribute to this balance by suppressing the apoptotic
pathway at multiple levels and by several mechanisms (Figure).
Inhibition of caspase activity by S-nitrosylation is the
best-characterized mechanism for the inhibition of apoptosis by
NO and is likely to be effective in cells that can efficiently carry
out S-nitrosylation. Higher rates of NO production
overwhelm cellular protective mechanisms and shift the balance toward
apoptotic death in some cell types. The presence of superoxide
may also divert NO to a toxic pathway by leading to the formation of
peroxynitrite. Further studies should continue to elucidate the many
factors that determine whether NO promotes or inhibits
apoptosis.
Acknowledgments
This work was supported by National Institutes of Health grant R01-GM-44100 and Korea Science and Engineering Foundation grant 981-0714-100-2.
Received September 24, 1998; accepted November 19, 1998.
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 X. Feng, Z. Guo, M. Nourbakhsh, H. Hauser, R. Ganster, L. Shao, and D. A. Geller Identification of a negative response element in the human inducible nitric-oxide synthase (hiNOS) promoter: The role of NF-kappa B-repressing factor (NRF) in basal repression of the hiNOS gene PNAS, October 29, 2002; 99(22): 14212 - 14217. [Abstract] [Full Text] [PDF]
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M. J. Szabolcs, J. Sun, N. Ma, A. Albala, R. R. Sciacca, G. B. Philips, J. Parkinson, N. Edwards, and P. J. Cannon Effects of Selective Inhibitors of Nitric Oxide Synthase-2 Dimerization on Acute Cardiac Allograft Rejection Circulation, October 29, 2002; 106(18): 2392 - 2396. [Abstract] [Full Text] [PDF]
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 C. V. Suschek, E. Bonmann, A. Kapsokefalou, K. Hemmrich, H. Kleinert, U. Forstermann, K.-D. Kroncke, C. Mahotka, and V. Kolb-Bachofen Revisiting an Old Antimicrobial Drug: Amphotericin B Induces Interleukin-1-Converting Enzyme as the Main Factor for Inducible Nitric-Oxide Synthase Expression in Activated Endothelia Mol. Pharmacol., October 1, 2002; 62(4): 936 - 946. [Abstract] [Full Text] [PDF]
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J. J. Boyle, P. L. Weissberg, and M. R. Bennett Human Macrophage-Induced Vascular Smooth Muscle Cell Apoptosis Requires NO Enhancement of Fas/Fas-L Interactions Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1624 - 1630. [Abstract] [Full Text] [PDF]
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J. Bartunek, M. Vanderheyden, M. W. M. Knaapen, W. Tack, M. M. Kockx, and M. Goethals Deoxyribonucleic acid damage/repairproteins are elevated in the failing human myocardium due to idiopathic dilated cardiomyopathy J. Am. Coll. Cardiol., September 18, 2002; 40(6): 1097 - 1103. [Abstract] [Full Text] [PDF]
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H. L. Li, J. Suzuki, E. Bayna, F.-M. Zhang, E. Dalle Molle, A. Clark, R. L. Engler, and W. Y. W. Lew Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes via cardiac AT1 receptors Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H461 - H467. [Abstract] [Full Text] [PDF]
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H. Funakoshi, T. Kubota, Y. Machida, N. Kawamura, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2159 - H2166. [Abstract] [Full Text] [PDF]
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C. GILL, R. MESTRIL, and A. SAMALI Losing heart: the role of apoptosis in heart disease--a novel therapeutic target? FASEB J, February 1, 2002; 16(2): 135 - 146. [Abstract] [Full Text] [PDF]
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 T. Kiviluoto, S. Watanabe, M. Hirose, N. Sato, H. Mustonen, P. Puolakkainen, M. Ronty, T. Ranta-Knuuttila, and E. Kivilaakso Nitric oxide donors retard wound healing in cultured rabbit gastric epithelial cell monolayers Am J Physiol Gastrointest Liver Physiol, November 1, 2001; 281(5): G1151 - G1157. [Abstract] [Full Text] [PDF]
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M. Jaiswal, N. F. LaRusso, and G. J. Gores Nitric oxide in gastrointestinal epithelial cell carcinogenesis: linking inflammation to oncogenesis Am J Physiol Gastrointest Liver Physiol, September 1, 2001; 281(3): G626 - G634. [Abstract] [Full Text] [PDF]
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J. He, Y. Xiao, and L. Zhang Cocaine-Mediated Apoptosis in Bovine Coronary Artery Endothelial Cells: Role of Nitric Oxide J. Pharmacol. Exp. Ther., July 1, 2001; 298(1): 180 - 187. [Abstract] [Full Text]
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 S. Pervin, R. Singh, C.-L. Gau, H. Edamatsu, F. Tamanoi, and G. Chaudhuri Potentiation of Nitric Oxide-induced Apoptosis of MDA-MB-468 Cells by Farnesyltransferase Inhibitor: Implications in Breast Cancer Cancer Res., June 1, 2001; 61(12): 4701 - 4706. [Abstract] [Full Text] [PDF]
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 M. MANDERSCHEID, U. K. MEßMER, R. FRANZEN, and J. PFEILSCHIFTER Regulation of Inhibitor of Apoptosis Expression by Nitric Oxide and Cytokines: Relation to Apoptosis Induction in Rat Mesangial Cells and RAW 264.7 Macrophages J. Am. Soc. Nephrol., June 1, 2001; 12(6): 1151 - 1163. [Abstract] [Full Text]
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M. J. Szabolcs, N. Ma, E. Athan, J. Zhong, M. Ming, R. R. Sciacca, J. Husemann, A. Albala, and P. J. Cannon Acute Cardiac Allograft Rejection in Nitric Oxide Synthase-2-/- and Nitric Oxide Synthase-2+/+ Mice : Effects of Cellular Chimeras on Myocardial Inflammation and Cardiomyocyte Damage and Apoptosis Circulation, May 22, 2001; 103(20): 2514 - 2520. [Abstract] [Full Text] [PDF]
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 G. Golderer, E. R. Werner, S. Leitner, P. Gröbner, and G. Werner-Felmayer Nitric oxide synthase is induced in sporulation of Physarum polycephalum Genes & Dev., May 15, 2001; 15(10): 1299 - 1309. [Abstract] [Full Text]
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 R. Roozendaal, E. Vellenga, M. A. de Jong, K. F. Traanberg, D. S. Postma, J. G. R. de Monchy, and H. F. Kauffman Resistance of activated human Th2 cells to NO-induced apoptosis is mediated by {{gamma}}-glutamyltranspeptidase Int. Immunol., April 1, 2001; 13(4): 519 - 528. [Abstract] [Full Text] [PDF]
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J. A. Beckman, A. Thakore, B. H. Kalinowski, J. R. Harris, and M. A. Creager Radiation therapy impairs endothelium-dependent vasodilation in humans J. Am. Coll. Cardiol., March 1, 2001; 37(3): 761 - 765. [Abstract] [Full Text] [PDF]
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 P. R. Murphy, M. Limoges, F. Dodd, R. T. M. Boudreau, and C. K. L. Too Fibroblast Growth Factor-2 Stimulates Endothelial Nitric Oxide Synthase Expression and Inhibits Apoptosis by a Nitric Oxide-Dependent Pathway in Nb2 Lymphoma Cells Endocrinology, January 1, 2001; 142(1): 81 - 88. [Abstract] [Full Text] [PDF]
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B. Beltran, A. Mathur, M. R. Duchen, J. D. Erusalimsky, and S. Moncada The effect of nitric oxide on cell respiration: A key to understanding its role in cell survival or death PNAS, December 19, 2000; 97(26): 14602 - 14607. [Abstract] [Full Text] [PDF]
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J. He, Y. Xiao, C. A. Casiano, and L. Zhang Role of Mitochondrial Cytochrome c in Cocaine-Induced Apoptosis in Coronary Artery Endothelial Cells J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 896 - 903. [Abstract] [Full Text]
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N. S. Chandel and J. I. Sznajder Stretching the lung and programmed cell death Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1003 - L1004. [Full Text] [PDF]
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 Y.-W. E. Chang, R. Jakobi, A. McGinty, M. Foschi, M. J. Dunn, and A. Sorokin Cyclooxygenase 2 Promotes Cell Survival by Stimulation of Dynein Light Chain Expression and Inhibition of Neuronal Nitric Oxide Synthase Activity Mol. Cell. Biol., November 15, 2000; 20(22): 8571 - 8579. [Abstract] [Full Text] [PDF]
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 S. A. Fisher, B. L. Langille, and D. Srivastava Apoptosis During Cardiovascular Development Circ. Res., November 10, 2000; 87(10): 856 - 864. [Abstract] [Full Text] [PDF]
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 M. Hesse, A. W. Cheever, D. Jankovic, and T. A. Wynn NOS-2 Mediates the Protective Anti-Inflammatory and Antifibrotic Effects of the Th1-Inducing Adjuvant, IL-12, in a Th2 Model of Granulomatous Disease Am. J. Pathol., September 1, 2000; 157(3): 945 - 955. [Abstract] [Full Text] [PDF]
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 J. Xu, L. He, S. H. Ahmed, S.-W. Chen, M. P. Goldberg, J. S. Beckman, C. Y. Hsu, and C. Iadecola Oxygen-Glucose Deprivation Induces Inducible Nitric Oxide Synthase and Nitrotyrosine Expression in Cerebral Endothelial Cells Editorial Comment Stroke, July 1, 2000; 31(7): 1744 - 1751. [Abstract] [Full Text] [PDF]
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 M. Sata, M. Kakoki, D. Nagata, H. Nishimatsu, E. Suzuki, T. Aoyagi, S. Sugiura, H. Kojima, T. Nagano, K. Kangawa, et al. Adrenomedullin and Nitric Oxide Inhibit Human Endothelial Cell Apoptosis via a Cyclic GMP-Independent Mechanism Hypertension, July 1, 2000; 36(1): 83 - 88. [Abstract] [Full Text] [PDF]
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 V. Pentikäinen, K. Erkkilä, L. Suomalainen, M. Parvinen, and L. Dunkel Estradiol Acts as a Germ Cell Survival Factor in the Human Testis in Vitro J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 2057 - 2067. [Abstract] [Full Text]
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S. Aiello, M. Noris, G. Piccinini, S. Tomasoni, F. Casiraghi, S. Bonazzola, M. Mister, M. H. Sayegh, and G. Remuzzi Thymic Dendritic Cells Express Inducible Nitric Oxide Synthase and Generate Nitric Oxide in Response to Self- and Alloantigens J. Immunol., May 1, 2000; 164(9): 4649 - 4658. [Abstract] [Full Text] [PDF]
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R. D. Rakhit, R. J. Edwards, J. W. Mockridge, A. R. Baydoun, A. W. Wyatt, G. E. Mann, and M. S. Marber Nitric oxide-induced cardioprotection in cultured rat ventricular myocytes Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1211 - H1217. [Abstract] [Full Text] [PDF]
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M. R. Ciriolo, A. De Martino, E. Lafavia, L. Rossi, M. T. Carri, and G. Rotilio Cu,Zn-Superoxide Dismutase-dependent Apoptosis Induced by Nitric Oxide in Neuronal Cells J. Biol. Chem., February 18, 2000; 275(7): 5065 - 5072. [Abstract] [Full Text] [PDF]
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I. Petrache, L. E. Otterbein, J. Alam, G. W. Wiegand, and A. M. K. Choi Heme oxygenase-1 inhibits TNF-alpha -induced apoptosis in cultured fibroblasts Am J Physiol Lung Cell Mol Physiol, February 1, 2000; 278(2): L312 - L319. [Abstract] [Full Text] [PDF]
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H. Yaoita, K. Ogawa, K. Maehara, and Y. Maruyama Apoptosis in relevant clinical situations: contribution of apoptosis in myocardial infarction Cardiovasc Res, February 1, 2000; 45(3): 630 - 641. [Abstract] [Full Text] [PDF]
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Y. Ono, H. Ono, H. Matsuoka, T. Fujimori, and E. D. Frohlich Apoptosis, Coronary Arterial Remodeling, and Myocardial Infarction After Nitric Oxide Inhibition in SHR Hypertension, October 1, 1999; 34(4): 609 - 616. [Abstract] [Full Text] [PDF]
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W. J Paulus and A. M Shah NO and cardiac diastolic function Cardiovasc Res, August 15, 1999; 43(3): 595 - 606. [Full Text] [PDF]
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H. Drexler Nitric Oxide Synthases in the Failing Human Heart : A Doubled-Edged Sword? Circulation, June 15, 1999; 99(23): 2972 - 2975. [Full Text] [PDF]
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J. Li and T. R. Billiar IV. Determinants of nitric oxide protection and toxicity in liver Am J Physiol Gastrointest Liver Physiol, May 1, 1999; 276(5): G1069 - G1073. [Abstract] [Full Text] [PDF]
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P. S. Brookes, E. P. Salinas, K. Darley-Usmar, J. P. Eiserich, B. A. Freeman, V. M. Darley-Usmar, and P. G. Anderson Concentration-dependent Effects of Nitric Oxide on Mitochondrial Permeability Transition and Cytochrome c Release J. Biol. Chem., June 30, 2000; 275(27): 20474 - 20479. [Abstract] [Full Text] [PDF]
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H. Funakoshi, T. Kubota, Y. Machida, N. Kawamura, A. M. Feldman, H. Tsutsui, H. Shimokawa, and A. Takeshita Involvement of inducible nitric oxide synthase in cardiac dysfunction with tumor necrosis factor-alpha Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2159 - H2166. [Abstract] [Full Text] [PDF]
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F. Gao, E. Gao, T.-L. Yue, E. H. Ohlstein, B. L. Lopez, T. A. Christopher, and X.-L. Ma Nitric Oxide Mediates the Antiapoptotic Effect of Insulin in Myocardial Ischemia-Reperfusion: The Roles of PI3-Kinase, Akt, and Endothelial Nitric Oxide Synthase Phosphorylation Circulation, March 26, 2002; 105(12): 1497 - 1502. [Abstract] [Full Text] [PDF]
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