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32 Shimizu S.: Tetrahydrobiopterin to Protect Cells from ROS- and NO-induced Injury

Pteridines Vol. 13. 2002. pp. 32 - 37

Protective Effect of Tetrahydrobiopterin Against Reactive Oxygen Species- and -induced Vascular Endothelial Cell Injury

Shuniehi Shimizu

Department of Pathophysiology, School of Pharmaceutical Sciences, Showa University, Tokyo 142-8555, Japan

Abstract

Vascular endothelial cells are one of the major biological targets of reactive oxygen species (ROS) in ischemia- reperfusion, , hypercholesterolemia and inflammation. Accumulated evidence has shown that tetrahy- drobiopterin (BTI4), which is an essential cefaclor for (NOS) activity, protected the cells against ROS and nitric oxide (NO) toxicities. Although NOS releases NO, which regulates vascular tone and immune surveillance under normal conditions, NOS also produces anion and hydrogen peroxide when BH4 is decreased, suggesting the possibility that NOS is a source of ROS under pathological conditions. Since 15114 is easily oxidized by ROS, may induce ROS release from NOS by the decomposition of BH4. ÖH4 also has an antioxidative activity and scavenging activity for ROS. In this review, the role of BH4 in the func- tion of' NOS, and the mechanisms underlying the protective effect of BFU against ROS- and/or NO-induced endothelial cell injury will be discussed.

Key words: nitric oxide synthase, nitric oxide, hydrogen peroxide, tetrahydrobiopterin, endothelial cells, cell injury

Introduction lbrm NOS III has also been confirmed (12-15). NO reacts w ith ROS such as superoxide anion and hydro- Nitric oxide (NO) is an important signaling mole- gen peroxide to form , singlet oxygen and cule for the regulation of vital functions such as vascu- hydroxvl radical, which are more toxic species (16- lar tone or neurotransmission and immune surveil- 10). Therefore, the simultaneous production of NO and lance. NO is synthesized by the conversion of 1.-argi- ROS by NOS in the presence of suboplimal concentra- nine to L-citrulline by NO synthase (NOS). There are tions of Bi b may lead to cytotoxicity. The BIU content 3 isofonns of NOS. including constitutive forms from of cells may be lowered in the presence of ROS, since neuronal cells (NOS 1 or nNOS) and endothelial cells it is easily oxidized by ROS. Under pathological con- (NOS 111 or eNOS), and an inducible form from ma- ditions such as hypercholesterolemia and diabetes mel- crophages, neutrophils and smooth muscle cells (NOS litus, the BH4 content is likely to be decreased (20-23). II or iNOS). All three isoforms of NOS require tetrahy- Therefore, it is possible that dysfunction of NOS may drobiopterin (]il 14) as a critical (1-4), which be an important factor in the development of many cir- has been well characterized as the electron donor for culatory diseases. Importantly, , including Bll-t, , and hydroxylases are putative and radical scavengers (24- (5-7). The of Βlk") can occur via a de 28). fhus. Bll-i is not only a cofactor for NOS, but also novo pathway from (OTP), in a regulator for NOS function (controlling the release of which the OTP cyclohydrolase 1 catalyzes the NO and or ROS) and a radical scavenger. In this re- rate-limiting step, or via a salvage pathway that utilizes view, we focus on the role of BH4 in vascular endothe- sepiaplerin during an intermediate step (8, 9). Inte- lial cell injury, and discuss the mechanisms of the pro- restingly, purified NOS 1 from the brain has been tective effects of Blh against cell injury induced by shown to produce reactive oxygen species (ROS) ROS and or NO. which are implicated in the develop- when ΒΠ4) and/or 1.- are decreased ( 10, 1 1). ment of many pathological states, including ischemia- Recently, the production of ROS by endothelial iso- reperftision injury, diabetes, inflammatory diseases.

Correspondence to: Shunichi Shimizu. Ph.D.. Department ol'Pathophysiology. School ol'Pharmaceutical Sciences. Showa University, 1-5-8 Hatanodai. Slnnagawa-ku. Tokyo 142-R555. Japan. Tel: -81-3-3784-8041. FAX: -81-3-3786-0481. F.-mail: shun.,; pharm.sboua-u.ac.ip

Ptendines/Vol. 13'No. I Shimizu S.: Tetrahydrobiopterin to Protect Cells from ROS- and NO-induced Injury 33

Dysfunction of NOS by oxidative stress and on Ca2Vcalmodulin (14). It is known that increases in endothelial cell injury intracellular Ca2* ([Ca3+]i) are involved in oxidative stress-induced lethal endothelial cell injury (41, 42). Reactive oxygen species are implicated in the We found that hydrogen peroxide markedly increases development of many diseases such as ischemia-reper- NOS activity by increasing [Ca2+]¡ several hours after fusion injury, inflammation and diabetes. NO has been addition in bovine aortic endothelial cells (43). The shown to react highly with superoxide anion and increases in NOS activity are observed before lethal hydrogen peroxide to produce cytotoxic species such cell injury. Thus, NOS activity, which is measured by as peroxynitrite and the hydroxyl radical (16-19). the conversion of L-arginine to L-citrulline, is stimu- Although NO has been shown to attenuate ischemia- lated during oxidative stress via an increase in [Ca2*]i reperfusion injury (29), hypoxia-reoxygenation injury before cell death (43). Although it has not been deter- (30) and ROS-induced cytotoxicity (31-33), there have mined whether NOS III produces NO or ROS before also been many reports of the toxic effects of NO in cell death, activation of NOS III before cell death may pathologic conditions, including ischemia-reperfusion, mainly produce ROS, since BH4 is easily oxidized by inflammation and diabetes mellitus (34-36). In 1994, ROS. These observations supported our hypothesis in the process of examining whether NO, produced that the production of ROS by NOS III is implicated in from endothelial cells during hydrogen peroxide treat- the hydrogen peroxide-induced vascular endothelial ment, modulates the hydrogen peroxide-induced cell cell injury. Thus, BH4 could be the most important tar- injury, we found that N°-nitro-L-arginine methyl ester get of oxidative stress in the vascular endothelial cells. (L-NAME), an inhibitor of NOS, reduces exogenous It is possible that dysfunction of NOS III accompanied hydrogen peroxide-induced endothelial cell injury, but by a decrease in the BH4 content causes a simultaneous that NG-methyl-L-arginine (L-NMA), also an inhibitor release of ROS and NO, and that the dysfunction of the of NO synthesis, does not, although both NOS enzyme may be involved in the development of many inhibitors completely blocked the NOS activity (37). diseases such as ischemia-reperfusion, hypercholes- Heinzel et al. (10) reported that purified NOS I from terolemia and diabetes. In fact, recent studies have the brain releases hydrogen peroxide instead of NO at shown the beneficial effects of BH4 on vascular low concentrations of L-arginine, a substrate for NO endothelial cell function in human and various experi- synthesis, or BH4, one of the cofactors for NO synthe- mental models (44-49). sis. Pou et al. (11) also showed that NOS I from brain produces superoxide anion. The production of super- Protective effect of BH4 against ROS-induced cell oxide anion by NOS I is inhibited by L-NAME, but not injury by L-NMA (10, 11). As for the mechanism of the pro- tective effect of L-NAME on hydrogen peroxide- We found that BH4 strongly reduced hydrogen per- induced endothelial cell injury, we speculated that L- oxide-induced cell injury in bovine aortic endothelial NAME inhibits the production of ROS by NOS III dur- cells (50). Pterins including BH4 have antioxidative ing oxidative stress-induced cell injury. In fact, NOS activity and scavenging activity for ROS. Shen and III has also been confirmed to release superoxide anion Zhang (51) first demonstrated that BH4 has antioxida- and hydrogen peroxide in the presence of suboptimal tive activity by showing that BH4 inhibits concentrations of BH4 (12-15). Moreover, there are autoxidation. Moreover, they suggested that the some suggestive data indicating that the production of BH4/NADH:BH4 system in rat phenochro- ROS from NOS III was inhibited by L-NAME. mocytoma (PC 12) cells has a protective effect against Pritchard et al. (38) showed that native low-density oxidative damage (52). However, the reaction mecha- lipoprotein enhances superoxide generation from NOS nism remains to be established. Kojima et al. (26) III in human umbilical vein endothelial cells, and the found that BH4 acts directly as a scavenger of super- generation of superoxide anion is inhibited by L- oxide anion generated by xanthine/xanthine oxidase or NAME. Cosentino and Katusic (39) reported that a by rat macrophage/phorbol myristate acetate radical- decrease in BH4 causes production of hydrogen perox- generating systems, and that paraquat-induced cyto- ide from NOS III in dog coronary arteries, and this toxicity of cultured hepatocytes is suppressed by BH4. production is prevented by L-NAME. We also showed The superoxide anion-scavenging activity of BH4 that vascular endothelial cells activated by Ca2*- seems to be stronger than that of ascorbic acid (26). ionophore produce superoxide anion when the BH4 Using 2',7'-dichlorofluorescin, a hydroperoxide-sensi- content in the cells is decreased, and the superoxide tive dye, we showed that BH4 reduces hydrogen per- anion release is inhibited by L-NAME (40). oxide-induced intracellular oxidative stress (50). In The production of ROS from NOS III is dependent contrast, BH4 has been shown to give rise to superox-

Pteridines/Vol. 13/No. 1 34 Shimizu S.: Tetrahydrobiopterin to Protect Cells from ROS- and NO-induced Injury

ide anion by autoxidation (53). We also observed that against NO cytotoxicity, Kojima et al. (58) argued that BH4 generates 2',7'-dichlorofluorescin-detectable ROS BH4 quenches NO, since BH4 reacts with 1,1-di- in the absence of cells (unpublished data). Therefore, phenyl-2-picrylhydrazyl, a stable radical, in an ethanol although whether or not extracellular BH4 scavenges solution. Although those results are important, the ROS is still controversial, intracellular BHU seems investigation was indirect. Further studies are needed mainly to play a role as a radical scavenger and/or to examine in detail whether or not BH4 scavenges antioxidant. Thus, BH4 has strong antioxidant activity, NO. and protects various cells against oxidative stress. ROS The BH4 content is increased along with the induc- are implicated in the development of many pathologi- tion of NOS II by treatment with LPS and/or cytokines cal states, such as ischemia-reperfusion injury, vascu- in several types of cells (65, 66). The expression of the lar dysfunction accompanying diabetes mellitus, mRNA for GTP-cyclohydrolase I, which is the rate- hypercholesterolemia, inflammation and Parkinso- limiting enzyme for BH4 synthesis, is also increased nism. BH4 may be useful in the treatment of various (65, 66). NOS II is composed of polypeptide homod- diseases which are related to ROS, since BHU has imers under native conditions. Dimerization of NOS II antioxidative and ROS scavenging activities, and requires the coincident presence of and BH4. improves the dysfunction of NOS, as discussed in the Gross and Levi (67) reported that BH4 synthesis is an iection of "Dysfunction of NOS by oxidative stress absolute requirement for the induction of NO synthesis ir.d endothelial cell injury·." by LPS in vascular smooth muscle cells. Nakayama et al. (68) also suggested that intracellular BH4 content Protective effect of tetrahydrobiopterin against was closely correlated with the induction of NOS II in NO-induced cell injury vascular smooth muscle cells, and the intracellular availability of BH4 has been shown to limit the expres- An inducible type of NOS is induced by sion of active NOS II dimers (69, 70). Thus, although hpopolysaccharide (LPS) and/or cytokines in various it is believed that an increase in the BH4 content is types of cells including vascular endothelial cells (54), required for the production of NO from inducible and this type of NOS continuously generates large NOS, the role of the increased BH4 that accompanies amounts of NO. The large amounts of NO have been NOS induction is not fully understood. We observed shown to induce lethal cell injury in the endothelial that an excess amount of BH4 is synthesized during cells (55-57). We and others have reported that NO NO production by NOS II in LPS-treated rat aorta donor S--N-acetyl-DL-penicillamine (SNAP)- (71). Mogi et al. (72) suggested that Β Ht has a self- induced cell injury is inhibited by exogenous BH4 in protective role in cytokine-induced apoptotic cell HL-60 cells (58) and the vascular endothelial cells death in mouse osteoblastic cells. It is possible that (59). Although the mechanisms of NO-induced cell BH4 plays a role in self-protection against the large injury remain unclear, the toxicities of NO-donors amounts of NO produced by NOS II, as another func- have been shown to be reduced by treatment with cata- tion. lase, but not with superoxide dismutase (SOD) (57, 59). Thus, cytotoxicity induced by NO is likely to be Conclusions mediated by endogenously produced hydrogen perox- ide. In fact, Asahi et al. (60, 61) have shown that glu- ROS are known to be implicated in many patholog- tathione peroxidase, which is part of the intracellular ical states, such as ischemia-reperfusion injury, inflam- hydrogen peroxide-scavenging system, is inactivated matory diseases, diabetes mellitus and hypercholes- by NO. Intracellular (GSH) content may terolemia. Generation of ROS by NOS accompanied also be decreased by reaction of GSH with NO to form by a decrease in the BH4 concentration was first report- S-mtroso-glutathione (62, 63). Depletion of GSH by ed for NOS I. Not only NOS I, but also NOS III, pro- GSH-depleting agents causes lethal cell injury, and the duces ROS when the BH4 concentration is decreased. cytotoxicity is mediated by ROS (64). Therefore, we BH4 seems to be one of the most important targets of speculated that endogenous production of hydrogen oxidative stress in the vascular endothelial cells. The peroxide caused by the treatment with NO is likely to NOS dysfunction is prevented by exogenous BH4. be involved in NO-induced cell injury, and that BH4 Moreover, BH4 protects the cells against ROS-induced protects cells against NO cytotoxicity at least partially cell injury by scavenging ROS such as superoxide by the scavenging of hydrogen peroxide as discussed anion and hydrogen peroxide. Interestingly, BH4 also in the section "Protective effect of BH4 against ROS- has a protective effect against NO-induced cytotoxici- induced cell injury." ty. ΒΙΊ4 may be useful m the treatment of various dis- As one of the mechanisms of protection by BH4 eases which are related to ROS and NO.

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