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© 2006 American Society for Nutrition J. Nutr. 136:2148-2152, August 2006

Biochemical, Molecular, and Genetic Mechanisms

The ACE Inhibitory Dipeptide Met-Tyr Diminishes Free Radical Formation in Human Endothelial Cells via Induction of Heme Oxygenase-1 and Ferritin1

Kati Erdmann, Nina Grosser, Katrin Schipporeit and Henning Schröder*

Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, 06099 Halle (Saale), Germany

* To whom correspondence should be addressed. E-mail: henning.schroeder{at}pharmazie.uni-halle.de.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Food sources such as soybeans and fish contain angiotensin I converting enzyme (ACE) inhibitory peptides with antihypertensive properties. Methionine-tyrosine (Met-Tyr) is an ACE inhibitory dipeptide derived from sardine muscle. The present study investigates the effect of Met-Tyr on the expression of the antioxidant stress proteins, heme oxygenase-1 (HO-1) and ferritin, in endothelial cells derived from the human umbilical vein and their contribution to the decrease in radical formation that occurs under the influence of this dipeptide. Preincubation of endothelial cells with Met-Tyr (10–300 µmol/L) followed by washout markedly diminished subsequently induced NADPH-mediated radical formation. This indirect protection was associated with a significant increase in protein expression of HO-1 and ferritin and abolished by the HO inhibitor zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG). The HO product bilirubin produced antioxidant effects comparable to those of Met-Tyr. Met-Tyr raised HO-1 mRNA levels by enhancing mRNA stability. Antioxidant effects were specific for Met-Tyr and not observed with other methionine-containing dipeptides or ACE inhibitory agents. Our results demonstrate that Met-Tyr protects endothelial cells from oxidative stress via induction of HO-1 and ferritin but independently of its ACE inhibitory properties. This pathway represents a novel, potentially antiatherogenic mechanism of Met-Tyr and dietary proteins releasing Met-Tyr during gastrointestinal digestion.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Cardiovascular disease is the leading cause of death in the Western world, despite the introduction of numerous preventive and therapeutic drug regimens over the last 2 decades. Recent dietary trials in secondary prevention of myocardial infarction reported a 70% decrease of the recurrence rate in patients consuming a Mediterranean diet (Lyon Diet Heart Study) (1–3). Consequently, increasing interest has focused on identifying dietary compounds that can diminish oxidative damage and therefore prevent the development of vascular diseases. Food-derived bioactive peptides represent one such source of health-enhancing components. These peptides are found in milk, meat, and fish of various kinds as well as in many plants. They are inactive within the sequence of their parent protein and can be released during gastrointestinal digestion or during food processing. Depending on the sequence of amino acids, these peptides can exhibit diverse activities, including opiate-like, immunomodulatory, antioxidant, antithrombotic, antimicrobial, and antihypertensive actions (4,5). Many of the known bioactive peptides reveal pleiotropic properties (6). Thus, the dipeptide Met-Tyr, which is derived from sardine muscle protein (7), possesses antihypertensive activities; along with similar dipeptides, it has received considerable attention for its antihypertensive effects in vivo (8–10). Met-Tyr and related dipeptides are thought to diminish blood pressure mostly by inhibition of angiotensin I converting enzyme (ACE)2 in the cardiovascular system. However, the exact mechanisms underlying their vasoprotective actions, which may well extend beyond the established ACE inhibitory effects, have not been identified.

Heme oxygenase-1 (HO-1) is an inducible enzyme that catalyzes the degradation of heme. This process leads to generation of carbon monoxide (CO), free iron, and biliverdin; the last mentioned is subsequently converted to bilirubin by biliverdin reductase. Bilirubin exerts strong antioxidant effects at physiological plasma concentrations. High-normal plasma levels of bilirubin were reported to be inversely related to atherogenic risk and to provide protection against endothelial damage (11,12). CO was similarly shown to produce antiapoptotic and cytoprotective actions (13,14). Furthermore, the HO-1–dependent release of free iron during heme catabolism results in the upregulation of ferritin protein expression. Ferritin was shown to provide marked antioxidant cellular protection by rapidly sequestering free cytosolic iron, the crucial catalyst of oxygen-centered radical formation via the Fenton reaction in biological systems (15,16). Thus, in addition to HO-1, ferritin plays an important role of its own as a fast-acting endogenous cytoprotectant in cellular antioxidant defense mechanisms (17,18).

We showed recently that single amino acids such as L-alanine and L-methionine are capable of inducing HO-1 and ferritin expression in endothelial cells (19,20). Therefore, induction of endothelial HO-1 followed by formation of its antioxidant enzymatic products could also contribute to the antihypertensive and tissue-protective properties of Met-Tyr and other food-derived ACE inhibitory peptides. The present study investigates whether HO-1 and ferritin are targets of Met-Tyr and act as functional antioxidant mediators for ACE inhibitory dipeptides in human endothelial cells (ECV304), which were established as a model cell line for endothelia (21).


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
    Materials. Fetal bovine serum, cell culture media, streptomycin, and penicillin were obtained from Gibco. PeqGOLD TriFast was received from Peqlab. The chemiluminescence western blotting kit was from Amersham and the random primed DNA labeling kit was from Roche. HO-1 primary antibody was obtained from Alexis. The dipeptides methionine-tyrosine, methionine-phenylalanine, and methionine-methionine were from Bachem. All other chemicals were purchased from Sigma Chemical. For HO-1 probes, the template was an EcoRI restriction fragment of the human HO-1 cDNA (clone 2/10), which was kindly provided by Dr. Rex Tyrrell, School of Pharmacy and Pharmacology, University of Bath, UK (22).

    Cell culture. The human endothelial cell line ECV304 was obtained from the European Collection of Cell Cultures (21). ECV304 endothelial cells were maintained and subcultured in M199 medium containing 10% fetal bovine serum, streptomycin (100 mg/L), and penicillin (100 kU/L). The cells were grown in a humidified incubator at 37°C and 5% CO2.

    Formation of ROS. The formation of NADPH-dependent reactive oxygen species (ROS) was measured by monitoring lucigenin-derived chemiluminescence at 37°C using the Berthold LB96V luminometer according to previously published protocols (19,23,24).

    HO-1 and ferritin protein analysis. Endothelial cells were cultured in 100-mm dishes as described above. After a 24-h incubation with control media or the indicated compounds, cells were washed and extracted. A polyclonal antibody to HO-1 and ferritin was used to identify the protein content as described previously (19,25).

    HO-1 mRNA analysis. Subconfluent endothelial cells in 100-mm dishes were incubated for 2–8 h in the presence of control media or Met-Tyr (300 µmol/L). For mRNA stability measurements, cells were incubated in the presence of the established HO-1 inducer cadmium chloride (CdCl2, 10 µmol/L). After 4 h, the cells were washed with cold PBS and the medium was changed. Subsequently, the inhibitor of transcription, actinomycin D (AD), was added to the cell culture medium at the final concentration of 1 mg/L 15 min before Met-Tyr. Cells were harvested after 2, 4, and 6 h. Total RNA was extracted using peqGOLD TriFast according to the instructions of the supplier. Briefly, samples containing equal amounts of RNA (20–30 µg) were separated in a 1% denaturing formaldehyde gel. Separated RNA was transferred onto a positively charged nylon membrane by vacuum transfer (500 mbar). The transferred RNA was fixed by baking at 80°C for 30 min. After 32P-labeling of a human HO-1 cDNA probe with a Random Primed DNA Labeling Kit, the membranes were hybridized overnight at 65°C. Equal loading was assessed by a second hybridization using 32P-labeled ß-actin cDNA probe. Quantification of HO-1 mRNA content was performed using computer-assisted videodensitometry.

    Statistical analysis. Results are expressed as means ± SEM. Data were analyzed by ANOVA and subsequently by Bonferroni's correction for multiple comparisons. An unpaired t test was used for pair-wise comparisons. All statistical calculations were performed using GraphPad Prism 3.02. Differences were considered significant at P < 0.05. Analyses were based on 3–6 independent experiments using different cell passages on different days.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Effect of Met-Tyr on HO-1 and ferritin. A 24-h incubation of endothelial cells with the ACE inhibitory dipeptide Met-Tyr (30–300 µmol/L) produced concentration-dependent increases in HO-1 protein levels (Fig. 1). HO-1 mRNA increased markedly and in a time-dependent manner after exposure of endothelial cells to Met-Tyr with a maximal stimulation to 1.5-fold (P = 0.1) of the control at 300 µmol/L Met-Tyr (Table 1). Therefore, we investigated whether Met-Tyr increases HO-1 protein expression through stabilization of HO-1 mRNA. After exposure of endothelial cells to the potent HO-1 inducer CdCl2, transcription was blocked by adding AD 15 min before Met-Tyr. The HO-1 mRNA levels were higher in AD/Met-Tyr–treated cells than in AD-treated cells (Fig. 2). Previous studies showed that HO-1 protein expression is accompanied by the induction of a secondary antioxidant protein, ferritin. Thus, we examined the effects of Met-Tyr on ferritin protein expression in endothelial cells. Immunoblot analysis demonstrated a marked increase in ferritin protein expression after a 24-h exposure to Met-Tyr (Fig. 3).


Figure 1
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  		Figure 1  Met-Tyr increases HO-1 protein expression in endothelial cells. Values are means ± SEM, n = 5. Means without a common letter differ, P < 0.05. A representative Western blot analysis is shown in the upper panel.

 

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  		TABLE 1 Effect of exposure to 300 µmol/L Met-Tyr on HO-1 mRNA levels in endothelial cells1

 

Figure 2
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  		Figure 2  Met-Tyr stabilizes HO-1 mRNA in CdCl2-treated cells in the presence of actinomycin D. Values are means ± SEM, n = 5. Means without a common letter differ, P < 0.05. A representative Northern blot analysis is shown in the upper panel.

 

Figure 3
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  		Figure 3  Met-Tyr increases ferritin protein expression in endothelial cells. Values are means ± SEM, n = 5. Means without a common letter differ, P < 0.05. A representative Western blot analysis is shown in the upper panel.

 
    Effect of Met-Tyr on ROS. NADPH-dependent ROS formation was diminished by up to 30% after a long-term preincubation of endothelial cells (24 h) with Met-Tyr (Fig. 4). To explore a potential involvement of HO-1 products such as bilirubin in the observed protection by Met-Tyr, the selective HO inhibitor zinc deuteroporphyrin IX 2,4-bis-ethylene glycol (ZnBG) was used. ZnBG abrogated cellular protection afforded by Met-Tyr against NADPH-mediated free radical formation (Fig. 4). In agreement with this, the HO-1 metabolite bilirubin, when added directly to the suspended cells, produced an almost complete inhibition of ROS formation (Fig. 5). Moreover, a Met-Tyr–induced blockade of free radical formation was prevented in the presence of the NO synthase inhibitor L-NG-monomethyl arginine (L-NMMA; Fig. 4). ZnBG or L-NMMA alone did not affect NADPH-mediated radical formation under these conditions (not shown).


Figure 4
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  		Figure 4  Met-Tyr diminishes NADPH-mediated superoxide formation in endothelial cells. This effect is reversed in the presence of the HO inhibitor ZnBG and the nitric oxide synthase inhibitor L-NMMA. Values are means ± SEM, n = 4. Means without a common letter differ, P < 0.05.

 

Figure 5
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  		Figure 5  Effect of bilirubin on NADPH-dependent ROS formation in endothelial cells. Values are means ± SEM, n = 3. Means without a common letter differ, P < 0.05.

 
    Effects of Met-Met, Met-Phe, and captopril on HO-1 and ROS. HO-1 protein induction by Met-Tyr was specific in that other ACE inhibitory compounds tested, such as the ACE inhibitory dipeptide Met-Phe and captopril, a sulfhydryl-containing clinically used ACE inhibitor, did not affect HO-1 protein levels (Table 2). The dipeptide Met-Met, which does not possess ACE inhibitory properties also did not induce HO-1 protein expression (Table 2). Met-Met, Met-Phe, or captopril did not diminish free radical formation in endothelial cells (Table 3).


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  		TABLE 2 Effects of Met-Tyr, Met-Met, Met-Phe, captopril, and single amino acids on HO-1 protein expression in endothelial cells1

 

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  		TABLE 3 Effects of Met-Tyr, Met-Met, Met-Phe, captopril, and single amino acids on ROS formation in endothelial cells1

 
    Effects of single amino acids on HO-1 and ROS. Furthermore, we investigated the effect of the free amino acids L-methionine and L-tyrosine alone and in combination at concentrations comparable to those used for the dipeptide Met-Tyr. Under these conditions, HO-1 protein expression was not affected in the presence of the single amino acids alone or in combination (Table 2). Free radical formation in endothelial cells remained unaltered in the presence of the free amino acids L-methionine and L-tyrosine alone or in combination at micromolar concentrations (Table 3).


   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
A large variety of bioactive peptides are generated at relevant physiological levels in the gut lumen during normal digestion. These peptides enter the circulation intact and are capable of producing biologic actions. Several ACE inhibitory peptides that affect the cardiovascular system and exert antihypertensive actions were isolated (26–29). However, the exact vasoprotective mechanisms of these peptides in hypertensive subjects remain unclear.

The present study demonstrates that the ACE inhibitory dipeptide Met-Tyr, derived from sardine muscle (7), stimulates expression of the antioxidant defense protein HO-1 in a concentration-dependent manner. Previous findings revealed that HO-1 protein expression is accompanied by the induction of a secondary antioxidant protein, ferritin. Met-Tyr produced increases in ferritin protein expression at concentrations that also resulted in HO-1 induction. The main physiological stimulus of ferritin protein synthesis is intracellular iron (30). Due to the Met-Tyr–mediated HO-1 induction, the amount of intracellularly available free iron is increased, which could facilitate the induction of ferritin protein expression. Pretreatment with Met-Tyr was associated with protection of endothelial cells from oxidative stress. Met-Tyr inhibited ROS formation, which was elicited by the addition of NADPH to the cells after washout of Met-Tyr. Based on these findings, it is plausible that Met-Tyr activates antioxidant signaling pathways resulting in a sustained protection even after removal of Met-Tyr. That HO-1 could mediate Met-Tyr activity under these conditions was demonstrated by the direct radical scavenging effect of the HO-1 product bilirubin. In agreement with this, we found that endothelial cell protection by Met-Tyr was abrogated in the presence of the HO inhibitor ZnBG, suggesting that HO-1 and its enzymatic products are indeed of functional relevance and responsible for the observed antioxidant actions. Recently, we demonstrated that the antioxidant defense protein HO-1 is an intracellular site of action for the amino acids L-alanine and L-methionine, which exert long-term cytoprotection (19,20). Moreover, it was shown that curcumin and caffeic acid phenethyl ester, 2 plant-derived polyphenolic compounds with antioxidant, antitumor, and anti-inflammatory properties, are potent inducers of HO-1 in vascular endothelial and neuronal cells (31–33).

Although we were not able to detect significant changes in HO-1 mRNA levels on the basis of Northern blot analysis, we found strong evidence that Met-Tyr stabilizes HO-1 mRNA. Treatment of endothelial cells with Met-Tyr markedly prolonged the half-life of HO-1 mRNA after exposure to the potent HO-1 inducer CdCl2. The induction of HO-1 expression by endogenous NO, an established HO-1–inducing signaling molecule (34–36), also involves post-transcriptional effects such as stabilization of HO-1 mRNA (37,38). Hence, NO could be a mediator of Met-Tyr–dependent antioxidant actions. This is further supported by our finding that an inhibitor of NO synthase (L-NMMA) abrogated Met-Tyr–induced radical scavenging. Interestingly, previously observed antioxidant effects of L-methionine at millimolar concentrations were also abrogated by a NO synthase inhibitor (19), pointing to the relevance of NO as a mediator for both functional dipeptides and single amino acids. Furthermore and in agreement with our observations presented here, it was reported that regulation of mammalian genes other than HO-1 by amino acids also has a post-transcriptional component affecting mRNA stability (39–41).

The effects of Met-Tyr on ROS formation and HO-1 expression were detected at micromolar concentrations, which are well within the range of the 50% inhibitory concentration for Met-Tyr–dependent ACE inhibitory activity (7,10). The single amino acids L-methionine and L-tyrosine, alone or in combination, did not produce any significant effects under these conditions. This points to a crucial role of the peptide bond in Met-Tyr and/or specific structural features of the dipeptide. Support for our observation comes from earlier studies demonstrating that the constituent amino acids of carnosine and related agents are far less effective antioxidants than their parent proteins (5,42).

The ACE inhibitory dipeptide Met-Phe, also derived from sardines (7), and the clinically used ACE inhibitor captopril did not affect HO-1 expression and ROS formation. Therefore, HO-1 induction by Met-Tyr can be assumed to occur independently of ACE inhibition. The methionine-containing dipeptide Met-Met, which does not inhibit ACE, also did not mimic the effects of Met-Tyr in the present study. These findings underline the unique role of Met-Tyr as a functional dipeptide with HO-1–inducing and antioxidant properties that are both unrelated to its ACE inhibitory action.

In summary, we demonstrated for the first time that the food-derived bioactive dipeptide Met-Tyr stimulates expression of the antioxidant defense proteins HO-1 and ferritin in endothelial cells. These genomic actions of Met-Tyr lead to sustained antioxidant cellular protection. In addition to its ACE inhibitory and blood pressure–lowering effects, HO-1 induction is a novel, potentially antiatherogenic mechanism of Met-Tyr and dietary proteins releasing Met-Tyr during gastrointestinal digestion.


   FOOTNOTES
 
1 Supported by BMBF grant "Nutrition and Atherosclerosis" (0312750 A). Back

2 Abbreviations used: ACE, angiotensin I converting enzyme; AD, actinomycin D; HO, heme oxygenase; L-NMMA, L-NG-monomethyl arginine; ROS, reactive oxygen species; ZnBG, zinc deuteroporphyrin IX 2,4-bis-ethylene glycol. Back

Manuscript received 20 March 2006. Initial review completed 10 April 2006. Revision accepted 8 May 2006.


   LITERATURE CITED
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 

1. Renaud S, de Lorgeril M, Delaye J, Guidollet J, Jacquard F, Mamelle N, Martin JL, Monjaud I, Salen P, Toubol P. Cretan Mediterranean diet for prevention of coronary heart disease. Am J Clin Nutr. 1995;61:1360S–7.[Abstract]

2. de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study. Circulation. 1999;99:779–85.[Abstract/Free Full Text]

3. de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, Guidollet J, Touboul P, Delaye J. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease. Lancet. 1994;343:1454–9.[Medline]

4. Meisel H. Biochemical properties of regulatory peptides derived from milk proteins. Biopolymers. 1997;43:119–28.[Medline]

5. Kitts DD, Weiler K. Bioactive proteins and peptides from food sources. Applications of bioprocesses used in isolation and recovery. Curr Pharm Des. 2003;9:1309–23.[Medline]

6. Korhonen H, Pihlanto A. Food-derived bioactive peptides—opportunities for designing future foods. Curr Pharm Des. 2003;9:1297–308.[Medline]

7. Matsufuji H, Matsui T, Seki E, Osajima K, Nakashima M, Osajima Y. Angiotensin I-converting enzyme inhibitory peptides in an alkaline protease hydrolyzate derived from sardine muscle. Biosci Biotechnol Biochem. 1994;58:2244–5.[Medline]

8. Kawasaki T, Seki E, Osajima K, Yoshida M, Asada K, Matsui T, Osajima Y. Antihypertensive effect of valyl-tyrosine, a short chain peptide derived from sardine muscle hydrolyzate, on mild hypertensive subjects. J Hum Hypertens. 2000;14:519–23.[Medline]

9. Matsufuji H, Matsui T, Ohshige S, Kawasaki T, Osajima K, Osajima Y. Antihypertensive effects of angiotensin fragments in SHR. Biosci Biotechnol Biochem. 1995;59:1398–401.[Medline]

10. Vercruysse L, Van Camp J, Smagghe G. ACE inhibitory peptides derived from enzymatic hydrolysates of animal muscle protein: a review. J Agric Food Chem. 2005;53:8106–15.[Medline]

11. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Vasc Biol. 1996;16:250–5.[Abstract/Free Full Text]

12. Mayer M. Association of serum bilirubin concentration with risk of coronary artery disease. Clin Chem. 2000;46:1723–7.[Abstract/Free Full Text]

13. Otterbein LE, Choi AM. Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol. 2000;279:L1029–37.[Abstract/Free Full Text]

14. Otterbein LE, Zuckerbraun BS, Haga M, Liu F, Song R, Usheva A, Stachulak C, Bodyak N, Smith RN, et al. Carbon monoxide suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. Nat Med. 2003;9:183–90.[Medline]

15. Balla G, Jacob HS, Balla J, Rosenberg M, Nath K, Apple F, Eaton JW, Vercellotti GM. Ferritin: a cytoprotective antioxidant stratagem of endothelium. J Biol Chem. 1992;267:18148–53.[Abstract/Free Full Text]

16. Cairo G, Tacchini L, Pogliaghi G, Anzon E, Tomasi A, Bernelli-Zazzera A. Induction of ferritin synthesis by oxidative stress. Transcriptional and post-transcriptional regulation by expansion of the "free" iron pool. J Biol Chem. 1995;270:700–3.[Abstract/Free Full Text]

17. Kim YM, Bergonia H, Lancaster JR Jr. Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. FEBS Lett. 1995;374:228–32.[Medline]

18. Juckett MB, Balla J, Balla G, Jessurun J, Jacob HS, Vercellotti GM. Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro. Am J Pathol. 1995;147:782–9.[Abstract]

19. Erdmann K, Grosser N, Schroder H. L-Methionine reduces oxidant stress in endothelial cells: role of heme oxygenase-1, ferritin, and nitric oxide. AAPS J. 2005;7:E195–200.[Medline]

20. Grosser N, Oberle S, Berndt G, Erdmann K, Hemmerle A, Schroder H. Antioxidant action of L-alanine: heme oxygenase-1 and ferritin as possible mediators. Biochem Biophys Res Commun. 2004;314:351–5.[Medline]

21. Suda K, Rothen-Rutishauser B, Gunthert M, Wunderli-Allenspach H. Phenotypic characterization of human umbilical vein endothelial (ECV304) and urinary carcinoma (T24) cells: endothelial versus epithelial features. In Vitro Cell Dev Biol Anim. 2001;37:505–14.[Medline]

22. Keyse SM, Tyrrell RM. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci U S A. 1989;86:99–103.[Abstract/Free Full Text]

23. Munzel T, Afanas'ev IB, Kleschyov AL, Harrison DG. Detection of superoxide in vascular tissue. Arterioscler Thromb Vasc Biol. 2002;22:1761–8.[Abstract/Free Full Text]

24. Li Y, Zhu H, Kuppusamy P, Roubaud V, Zweier JL, Trush MA. Validation of lucigenin (bis-N-methylacridinium) as a chemilumigenic probe for detecting superoxide anion radical production by enzymatic and cellular systems. J Biol Chem. 1998;273:2015–23.[Abstract/Free Full Text]

25. Grosser N, Abate A, Oberle S, Vreman HJ, Dennery PA, Becker JC, Pohle T, Seidman DS, Schroder H. Heme oxygenase-1 induction may explain the antioxidant profile of aspirin. Biochem Biophys Res Commun. 2003;308:956–60.[Medline]

26. Masuda O, Nakamura Y, Takano T. Antihypertensive peptides are present in aorta after oral administration of sour milk containing these peptides to spontaneously hypertensive rats. J Nutr. 1996;126:3063–8.[Abstract/Free Full Text]

27. Matsui T, Tamaya K, Seki E, Osajima K, Matsumo K, Kawasaki T. Absorption of Val-Tyr with in vitro angiotensin I-converting enzyme inhibitory activity into the circulating blood system of mild hypertensive subjects. Biol Pharm Bull. 2002;25:1228–30.[Medline]

28. Matsui T, Tamaya K, Seki E, Osajima K, Matsumoto K, Kawasaki T. Val-Tyr as a natural antihypertensive dipeptide can be absorbed into the human circulatory blood system. Clin Exp Pharmacol Physiol. 2002;29:204–8.[Medline]

29. Vermeirssen V, Van Camp J, Verstraete W. Bioavailability of angiotensin I converting enzyme inhibitory peptides. Br J Nutr. 2004;92:357–66.[Medline]

30. Oberle S, Polte T, Abate A, Podhaisky HP, Schroder H. Aspirin increases ferritin synthesis in endothelial cells: a novel antioxidant pathway. Circ Res. 1998;82:1016–20.[Abstract/Free Full Text]

31. Hill-Kapturczak N, Thamilselvan V, Liu F, Nick HS, Agarwal A. Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cells. Am J Physiol Renal Physiol. 2001;281:F851–9.[Abstract/Free Full Text]

32. Motterlini R, Foresti R, Bassi R, Green CJ. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radic Biol Med. 2000;28:1303–12.[Medline]

33. Scapagnini G, Foresti R, Calabrese V, Giuffrida Stella AM, Green CJ, Motterlini R. Caffeic acid phenethyl ester and curcumin: a novel class of heme oxygenase-1 inducers. Mol Pharmacol. 2002;61:554–61.[Abstract/Free Full Text]

34. Polte T, Abate A, Dennery PA, Schroder H. Heme oxygenase-1 is a cGMP-inducible endothelial protein and mediates the cytoprotective action of nitric oxide. Arterioscler Thromb Vasc Biol. 2000;20:1209–15.[Abstract/Free Full Text]

35. Yee EL, Pitt BR, Billiar TR, Kim YM. Effect of nitric oxide on heme metabolism in pulmonary artery endothelial cells. Am J Physiol. 1996;271:L512–8.

36. Durante W, Kroll MH, Christodoulides N, Peyton KJ, Schafer AI. Nitric oxide induces heme oxygenase-1 gene expression and carbon monoxide production in vascular smooth muscle cells. Circ Res. 1997;80:557–64.[Abstract/Free Full Text]

37. Hartsfield CL, Alam J, Cook JL, Choi AM. Regulation of heme oxygenase-1 gene expression in vascular smooth muscle cells by nitric oxide. Am J Physiol. 1997;273:L980–8.

38. Bouton C, Demple B. Nitric oxide-inducible expression of heme oxygenase-1 in human cells. Translation-independent stabilization of the mRNA and evidence for direct action of nitric oxide. J Biol Chem. 2000;275:32688–93.[Abstract/Free Full Text]

39. Rinehart CA Jr, Canellakis ES. Induction of ornithine decarboxylase activity by insulin and growth factors is mediated by amino acids. Proc Natl Acad Sci U S A. 1985;82:4365–8.[Abstract/Free Full Text]

40. Chen ZP, Chen KY. Mechanism of regulation of ornithine decarboxylase gene expression by asparagine in a variant mouse neuroblastoma cell line. J Biol Chem. 1992;267:6946–51.[Abstract/Free Full Text]

41. Kanamoto R, Boyle SM, Oka T, Hayashi S. Molecular mechanisms of the synergistic induction of ornithine decarboxylase by asparagine and glucagon in primary cultured hepatocytes. J Biol Chem. 1987;262:14801–5.[Abstract/Free Full Text]

42. Alabovsky VV, Boldyrev AA, Vinokurov AA, Shchavratsky V. Effect of histidine-containing dipeptides on isolated heart under ischemia/reperfusion. Biochemistry (Mosc). 1997;62:77–87.[Medline]





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