Published online before print February 4, 2008, doi: 10.1161/HYPERTENSIONAHA.107.104570
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(Hypertension. 2008;51:696.)
© 2008 American Heart Association, Inc.
Original Articles |
Effect of Telmisartan on Nitric Oxide–Asymmetrical Dimethylarginine System
Role of Angiotensin II Type 1 Receptor and Peroxisome Proliferator Activated Receptor 
Signaling During Endothelial Aging
From the Institute of Clinical Pharmacology (F.S., J.M.-L., S.M.B.-B.) and the Institute of Experimental Internal Medicine (A.B., U.L.), University Hospital Otto-von-Guericke University, and IMTM (M.T.), Magdeburg, Germany.
Correspondence to Prof Dr Stefanie M. Bode-Böger, Institute of Clinical Pharmacology, University Hospital, Otto-von-Guericke University, Leipziger Strasse 44, D-39120 Magdeburg, Germany. E-mail stefanie.bode-boeger{at}med.ovgu.de
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Abstract |
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Telmisartan, in addition to blocking angiotensin (Ang) II type 1 receptor (AT1R), activates peroxisome proliferator activated receptor
(PPAR) signaling that interferes with nitric oxide (NO) system. Because aging of endothelial cells (ECs) is hallmarked by a reduction in NO synthesis, we hypothesized that telmisartan increases NO formation by regulated asymmetrical dimethylarginine (ADMA)-dimethylarginine dimethylaminohydrolase (DDAH)-system through blocking AT1R and activating PPAR signaling. To test this hypothesis, ECs were cultured with telmisartan, eprosartan, Ang II, and GW9662 (PPAR antagonist) until the twelfth passage. During the process of aging, PPAR protein expression decreased significantly, whereas the expression of AT1R increased. Telmisartan reversed these effects and dose-dependently decreased reactive oxygen species and 8-iso-prostaglandin (PG) F2
formation. This effect was associated with an upregulated activity and protein expression of DDAH, accompanied by a decrease in ADMA concentration, an increase in NO metabolites, and delayed senescence. Blockade of PPAR signaling by GW9662 or PPAR small-interference RNA prevented the effect of telmisartan on ADMA-DDAH-NO system. Coincubation with Ang II did not affect the effect of telmisartan-delayed senescence, whereas Ang II itself accelerated endothelial aging. Moreover, AT1R blocker eprosartan that did not influence PPAR protein expression had no effect on ADMA system and senescence. We have demonstrated that telmisartan mainly by activating PPAR signaling can alter the catabolism and release of ADMA as an important cardiovascular risk factor. We therefore propose that telmisartan translationally and posttranslationally upregulated DDAH expression via activation of PPAR signaling, causing ADMA to diminish and increase NO synthesis sufficient to delay senescence.
Key Words: telmisartan • angiotensin II type 1 receptor • peroxisome proliferator activated receptor • oxidative stress • asymmetrical dimethylarginine • nitric oxide • aging
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Introduction |
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Aging is a well-documented risk factor for cardiovascular diseases. One of the possible physiopathological mechanisms through which increasing age may lead to cardiovascular damage is the promotion of endothelial dysfunction.1 Aged human endothelial cells (ECs), which produce less NO, more asymmetrical dimethylarginine (ADMA), a novel cardiovascular risk factor, and more reactive oxygen species (ROS),2–5 could account for endothelial dysfunction and development of cardiovascular diseases.6–10 We and other have previously demonstrated that aging of human ECs can be altered by several different factors contributing to delay or accelerate the process of aging.2–5,11,12 These results suggest that the process of endothelial aging may be an influenceable process and raise the possibility of therapies for preventing various cardiovascular diseases in the elderly.
Telmisartan, a highly lipophilic angiotensin (Ang) II type 1 receptor (AT1R) blocker (ARB), is used for the treatment of hypertension.13 Besides its effect on blood pressure, telmisartan reduces atherosclerosis in apolipoprotein E– deficient mice via decreased oxidative stress.14 Moreover, telmisartan improves endothelial function in human15 and animal16,17 models by influencing the NO system. Recent studies have shown that telmisartan, in comparison to other ARBs when tested at concentrations that may be achievable in plasma after administration of doses used for the treatment of essential hypertension, activates also peroxisome proliferator activated receptor (PPAR) ,18 a nuclear hormone receptor and a well-known target of antidiabetic drugs. This effect appears to be independent of its AT1R blocking actions.19
PPAR signaling has important antiatherogenic properties20 and is associated with decreased oxidative stress21 and increased NO formation,22 which are 2 of the most important component affecting the process of aging in ECs.2–5,11,12
On the basis of these observations, we examined the effect of telmisartan on oxidative stress as well as ADMA-NO pathway through AT1R or PPAR signaling during aging of ECs.
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Methods |
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Cell Culture
Human umbilical vein endothelial cells (HUVECs, Clonetics/Cambrex, Verviers, Belgium) were cultured until twelfth passage and characterized as previously described.2 Telmisartan (1, 5, and 10 µmol/L), eprosartan (10 µmol/L), angiotensin II (Ang II, 100 nmol/L), and GW9662 (10 µmol/L) were replaced every 48 hours starting at the fourth passage. All above-mentioned products were delivered by Sigma except for eprosartan (Kemprotec Limited). Telmisartan, eprosartan, and GW9662 were dissolved in dimethyl sulfoxide (DMSO), Ang II in water. Control conditions included HUVECs treated with DMSO alone. Final DMSO concentrations in culture medium was 0.23% (v/v).
Treatment With PPAR Small Interfering RNA
HUVECs (passage 12) were grown in 6-well plates until 60% to 70% confluence and transiently transfected with PPAR or control small interfering RNA (siRNA) using the siRNA transfection reagent (Santa Cruz Biotechnology) according to the manufacturer’s instructions. PPAR siRNA sequence was as follows (human PPAR mRNA, GenBank accession number NM_005037): GCCCUUCACUACUGUUGACTT. The final concentration of siRNA in each well was 100 nmol/L. At 18 hours after transfection, cell were washed and resuspended in new culture media in the presence or absence of telmisartan for up to 48 hours. Sample were then prepared and analyzed for senescence, Western blot, and ADMA.
Detection of Oxidative Stress
Dihydrorhodamin 123 (DHR) was used as a marker for intracellular ROS and measured as described previously.2
For the determination of 8-iso-PG F2 (8-iso-PGF2) in cell culture supernatant we adopted the high-performance liquid chromatography (HPLC)-tandem mass spectrometry method described by Bohnstedt et al.23 The limit of detection for 8-iso-PGF2 was 1.5 pg/mL, and the relative standard deviation was 6.8%.
DDAH Activity
The enzyme activity of dimethylarginine dimethylaminohydrolase (DDAH) in cell lysates was assayed as described earlier.2
Determination of ADMA
For the determination of ADMA in cell culture supernatants we adopted the HPLC-mass spectrometry method published recently by our group.2 The limit of detection was found to be 0.03 µmol/L for ADMA. The intraday precision was 4.65%, the interday precision was 3.3%.
Measurement of Nitrate and Nitrite
For the determination of nitrate and nitrite (NOx) production, aliquots of culture supernatants were collected, centrifuged, and measured by gas chromatography-mass spectrometry as previously reported.2 In our laboratory, the intraday precision test yields a relative standard deviation of 3.8% for nitrite and 1.3% for nitrate, respectively. The interday precision test yields a relative standard deviation of 4.4% for nitrite and 4.2% for nitrate.
Detection of Senescence
HUVECs were fixed and stained for senescence-associated β-galactosidase (SA β-gal) activity according to the procedure described by Dimri et al.24
Western Blot Analysis
Western blotting was performed as described recently,25 with some modifications. Total cellular protein was measured using a BCA protein assay kit (Pierce). The primary antibodies to AT1R (1:200), DDAH II (1:500), and PPAR (1:500) were obtained from Santa Cruz Biotechnology. The second antibody (1:500) was purchased from Cell Signaling. To confirm that equal amounts of the protein were subjected to the Western blotting analysis, the membranes were reprobed with anti-GAPDH (1:500, Chemicon International). Quantification of the Western blots was performed by densitometry and the relative ratio to GADPH expression was calculated in each sample.
Statistical Methods
Results are expressed as mean±SEM. Statistical significance was tested with repeated-measures ANOVA by using a least-significant difference (LSD) post hoc test, or ANOVA for multiple comparisons (SPSS Software 13.0). Differences were considered to be significant at a value of P<0.05.
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Results |
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Telmisartan Delayed Endothelial Senescence, Downregulated AT1R, and Upregulated PPAR
Protein ExpressionTo investigate the effect of telmisartan on senescence, human endothelial cells (ECs) were cultured until passage 12 (old) and every 48 hours stimulated with telmisartan (10 µmol/L) starting from passage 4 (young). During serial passages of ECs, the activity of SA β-gal increased 10-fold in old cells compared with young cells. A long-term treatment with telmisartan decreased significantly SA β-gal positive cells (Figure 1A). To determine whether this effect was specific to telmisartan, eprosartan the other subclass of ARBs was used. In contrast to telmisartan, eprosartan induced no alteration of SA β-gal activity (Figure 1A). Moreover, coincubation with pathophysiologically relevant concentration of Ang II (100 nmol/L) did not influence the effect of telmisartan-delayed senescence, whereas Ang II itself increased significantly SA β-gal–positive cells (Figure 1B). From these data we would speculate that the effect of Ang II on senescence is mainly mediated by AT1R.
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Recent reports have demonstrated that telmisartan, in addition to blocking AT1R signaling, activates PPAR signaling.18,19 Also, we examined whether telmisartan delays senescence via PPAR signaling. Simultaneous incubation with a selective PPAR antagonist GW9662 (Figure 1C) inhibited significantly the telmisartan-induced decrease in SA β-gal–positive cells. GW9662 itself had no significant effect on SA β-gal–positive cells. To further examine whether the effect of telmisartan on senescence was mediated through activation of PPAR, cells were transfected with PPAR siRNA. Knock down of PPAR gene was confirmed by detecting protein expression. PPAR siRNA suppressed significantly PPAR protein expression in presence or absence of telmisartan. Control siRNA had no effect (Figure 2D). The knock down of PPAR by siRNA abolished the ability of telmisartan to delay endothelial senescence. Control siRNA had no effect (Figure 1D).
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To provide insight into cellular mechanism of telmisartan-delayed senescence, the protein expression of AT1R and PPAR was determined. During the process of endothelial aging, the expression of AT1R increased more than 2-fold. Telmisartan prevented the increase in AT1R expression but not eprosartan (Figure 2A). Coincubation with GW9662 (Figure 2A) or transfection with PPAR siRNA (Figure 2B) significantly abolished AT1R suppression induced by telmisartan. Furthermore, Western blot analysis showed a significant reduction in PPAR protein expression in old cells compared with young cells. Incubation with telmisartan upregulated PPAR expression above 2.5-fold compared with old control. Presuming that AT1R activation by Ang II suppress PPAR expression, then blocking of AT1R by telmisartan could have stimulated the suppressed expression. Ang II itself did not affect the PPAR expression as well as the AT1R blocker eprosartan (Figure 2C). These data suggest that the stimulatory activity of telmisartan is evoked via a mechanism independent of AT1R signaling.
Telmisartan Decreased Oxidative Stress and Upregulated the Activity and Protein Expression of DDAH II
As previously shown by us2,5 and confirmed in this study, the intracellular level of ROS increased 3-fold in old control compared with young control. The addition of therapeutically relevant concentrations of telmisartan (1, 5, and 10 µmol/L) resulted in a dose-dependent reduction of ROS formation (Figure 3A). Blockade of PPAR signaling by GW9662 abolished the effect of telmisartan on ROS. Coincubation with Ang II did not influence the effect of telmisartan-decreased ROS, whereas Ang II itself increased significantly the ROS formation (Figure 3B).
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The increased intracellular level of ROS was accompanied by 4-fold increase of extracellular level of 8-iso-PGF2 in old cells compared with young cells. Incubation with telmisartan decreased significantly 8-iso-PGF2 concentration. The effect of telmisartan-induced reduction in 8-iso-PGF2 formation was reversed in the presence of GW9662 (Figure 3C).
DDAH, the enzyme that degrades ADMA, is regulated in a redox-sensitive fashion.26 To test whether telmisartan-reduced oxidative stress upregulated the activity of DDAH, we determined DDAH activity by assessing the rate of degradation of exogenous ADMA added to the cell lysates. Concomitantly with the significant increase in ROS, the activity of DDAH decreased and reached the value of 44.77±4.64% in old cells. Incubation with telmisartan upregulated significantly the DDAH activity. Antagonizing PPAR signaling with GW9662 blocked telmisartan-upregulated DDAH enzyme activity, but no coincubation with Ang II (Figure 4A).
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To determine whether the increased DDAH activity in telmisartan-treated cells was correlated with an upregulation in protein expression, DDAH protein expression was measured in ECs using a monoclonal DDAH II antibody. Western blot analysis revealed that DDAH II protein expression was decreased significantly in old cells compared with young cells. Telmisartan increased 2-fold the protein expression of DDAH II compared with old control. Coincubation with Ang II did not influence the effect of telmisartan on DDAH expression. GW9662 (Figure 4B) or PPAR siRNA (Figure 4C) significantly reversed the effect of telmisartan on DDAH expression. The AT1R blocker eprosartan had no effect on DDAH II protein expression (data not shown).
Telmisartan Induced NO Synthesis by Decreasing Concentration of ADMA
To confirm that telmisartan enhanced DDAH activity, the ADMA concentrations were measured by HPLC analysis in conditioned media. The downregulation of DDAH activity and expression was associated with a 4-fold increase in ADMA concentration in the conditioned medium of old cells compared with young cells. As predicted, the addition of telmisartan decreased significantly the ADMA concentration, but not the AT1R blocker eprosartan (Figure 5A). Ang II itself increased significantly ADMA concentration, whereas it did not influence the effect of telmisartan-decreased ADMA concentration (Figure 5A). The inhibitory effect of telmisartan on ADMA was reversed by coincubating the cells with GW9662 (Figure 5A) or by transfection with PPAR siRNA (Figure 5B). Because ADMA levels were decreased by supplemental telmisartan, we hypothesized that this lowering of ADMA results in enhancement of NO availability. NOx synthesis decreased 50% in cell culture supernatants of old cells compared with young cells. Telmisartan augmented dose-dependently the NOx formation (Figure 5C). Addition of GW9662 significantly blocked the effect of temisartan on NOx secretion, but coincubation with Ang II did not affect the effect of telmisartan on NOx synthesis (Figure 5D).
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Discussion |
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The present study demonstrates for the first time that telmisartan delays EC senescence mainly by activating PPAR
signaling. This effect is associated with an upregulation of PPAR and downregulation of AT1R protein level and a decrease in oxidative stress. This leads to an enhancement in the activity and expression of DDAH, and consequently a decrease in ADMA concentration and an increase in NO synthesis. Endothelial aging is associated with marked changes in gene expression. The mRNA levels of AT1R are markedly upregulated in freshly isolated cardiomyocytes and in isolated perfused hearts from senescent rats,27,28 whereas mRNA and protein levels of PPAR are downregulated in adipose tissue of aged subjects and rats.29 The interaction between aging, AT1R, and PPAR expression in cultured ECs is likely a novel mechanism. We found that protein expression of AT1R was increased during EC aging, whereas PPAR protein levels were decreased. Recently, it has been demonstrated that the activation of PPAR signaling by telmisartan downregulates the expression of AT1R at both mRNA and protein levels in vascular smooth muscle cells from the thoracic aorta of Wistar-Kyoto rat. The suppression of AT1R occurs at transcriptional level and is independent of PPAR response element.30
Consistent with these findings, we showed that telmisartan downregulated AT1R protein expression by activation of PPAR signaling. The involvement of PPAR signaling on AT1R suppression was confirmed by using the PPAR antagonist GW9662 or by suppressing PPAR gene with PPAR siRNA.
Schupp et al31 reported that telmisartan downregulates moderately PPAR expression in murine and human adipocytes. Because a specific property of agonists for certain nuclear receptors is the downregulation of the receptor on mRNA or protein level on ligand activation, the authors speculated that telmisartan, as a partial agonist of nuclear receptor PPAR, may negatively autoregulate PPAR expression. In contrast, Jung et al32 have recently demonstrated that telmisartan induces the expression of PPAR in the intracerebral hemorrhage rat model. In the present study, we showed that telmisartan upregulated the protein level of PPAR via a mechanism independent of AT1R blockade in EC during aging. The activation of AT1R signaling by Ang II or blockade of AT1R signaling by eprosartan neither suppressed nor stimulated PPAR expression. Our findings are in accordance with in vivo studies demonstrating that the activation of angiotensin signaling by Ang II–infused rats has no effect on the expression and activity of PPAR.33 Furthermore, 24-hour incubation with 10 µmol/L eprosartan did not affect PPAR mRNA or protein expression in 3T3-L1 and human adipocytes.31
AT1R, a member of the superfamily G protein–coupled receptor, mediates most of the well–known pathophysiological effects of Ang II. In ECs, AT1R activation by Ang II increases ROS production by enhancement of expression and activity of NAD(P)H oxidase.34 This effect leads to specific inhibition of dihydrofolate reductase, decreased tetrahydrobiopterin bioavailability, and uncoupling of eNOS contributing to increase further the ROS formation.35 Telmisartan may exert beneficial effects on endothelial function by reducing AT1R-dependent production of oxygen radicals. This is strongly supported by experimental data indicating that the increase of endothelial superoxide production and NADPH oxidase activity in apolipoprotein E–deficient mice can be prevented with AT1R blocker telmisartan.16 Besides, telmisartan inhibited AGE-induced ROS generation via PPAR activation in human hepatoma Hep3B cells.36 PPAR, a ligand-activated transcription factor belonging to the nuclear receptor superfamily, regulates gene expression of key proteins involved in lipid metabolism, vascular inflammation, and proliferation, providing protection against atherosclerosis and coronary events.37 Recently, Yang et al38 have demonstrated that PPAR activation lowers the ROS levels through coordinated transcriptional control of a set of proteins and enzymes involved in ROS metabolism. PPAR increases the amount of uncoupling protein 2 and superoxide dismutase and reduces the amount of the p67 subunit of NADPH oxidase at both the mRNA and protein levels in T lymphoma cell lines.
A large body of evidence suggest that NADPH oxidase,28 mitochondria,3 and dysfunctional eNOS5 increase the formation of ROS during the process of EC aging. In the present study, we confirmed the ROS activation and showed for the first time a significant increase in8-iso-PGF2 level, a systemic oxidative stress marker, in aged ECs compared with young cells. The long-time treatment with telmisartan prevented dose-dependently the increased oxidative stress by activation of PPAR signaling, indicating the important role of PPAR pathways on the regulation of oxidative stress during endothelial aging.
The activity of the enzyme DDAH, which metabolizes ADMA to citrulline and dimethylamine, seems to be particularly susceptible to inhibition by oxidative stress. A wide range of pathological stimuli as well as aging induce endothelial oxidative stress and consequently reduce DDAH activity in vitro and in vivo with a corresponding accumulation of ADMA.2,26 The critical role of DDAH in regulating ADMA levels in vivo was demonstrated by using a transgenic DAAH mouse, by deleting the DDAH gene in mice and by using DDAH-specific inhibitors.39,40 Loss of DDAH function results in enhanced ADMA level and thereby in reduced NO signaling causing endothelial dysfunction.40 Two isoforms of DDAH have been identified in every cell type examined: DDAH I is typically found in tissue that express neuronal NOS, whereas DDAH II in tissue that contains endothelial NOS.41 The expression of DDAH II, but not DDAH I, has been also shown to be transcriptionally or translationally regulated.9,26 Analysis of the DDAH II promotor gene revealed the presence of a PPAR-binding site at the –927 position.42 PPAR ligand directly upregulated DDAH II expression at both transcriptional and translational levels in vitro and in vivo.43
In the present experiment, the approximate 50% decreases in both activity and protein expression of DDAH were observed during endothelial aging associated with 4-fold increase in ADMA level and a half reduction of NO synthesis. The long-time treatment with telmisartan markedly upregulated activity and protein expression of DDAH II by activation of PPAR signaling, which was reversed by coincubation with PPAR antagonist GW9662 or by transfection with siRNA PPAR. These results suggested that telmisartan upregulated DDAH II at translational and posttranslational level, which further induced the reduction in ADMA concentration and the increase in NO formation.
We and others have previously reported the important role of NO in the regulation of endothelial senescence.2,11 Incubation with NO donors delays the process of senescence.11 Moreover, the inhibition of NO synthesis by pathophysiological concentration of ADMA accelerates the course of endothelial senescence.2
Taken together, our study suggests that an upregulation of DDAH activity and protein expression might be involved in telmisartan-modulated ADMA-NO system sufficient to delay EC senescence.
Perspectives
Aging of human ECs is characterized by impaired NO bioavailability which could account for endothelial dysfunction and development of cardiovascular diseases. Telmisartan increases NO bioavailability by decreasing ADMA concentration during endothelial aging. Our study suggests that telmisartan, mainly by activating PPAR signaling, may play an important role as an "anti-aging" drug. Studies in animals and human after telmisartan treatment are needed to test the clinical relevance of our mechanistic results. This might provide a therapeutic strategy aimed at blocking aging-induced NO inhibition.
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Acknowledgments |
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The authors thank Dagmar Peters and Donate Zander for technical assistance and Kerstin Winkelmann for secretarial assistance.
Source of Funding
The work was supported in part by Bayer Vital GmbH, Leverkusen, Germany.
Disclosures
None.
Received November 7, 2007; first decision December 6, 2007; accepted January 8, 2008.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Quyyumi AA. Endothelial function in health and diseases: new insights into the genesis of cardiovascular disease. Am J Med. 1998; 105: 32S–39S.[Medline] [Order article via Infotrieve]
2. Scalera F, Borlak J, Beckmann B, Martens-Lobenhoffer J, Thum T, Täger M, Bode-Böger SM. Endogenous nitric oxide synthesis inhibitor asymmetric dimetlyl L-arginine accelerates endothelial cell senescence. Arterioscler Thromb Vasc Biol. 2004; 24: 1816–1822.
3. Haendeler J, Hoffmann J, Diehl JF, Vasa M, Spyridopoulos I, Zeiher AM, Dimmeler S. Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. Circ Res. 2004; 94: 768–775.
4. Bode-Böger SM, Martens-Lobenhoffer J, Täger M, Schröder H, Scalera F. Aspirin reduces endothelial cell senescence. Biochem Biophys Res Commun. 2005; 334: 1226–1232.[CrossRef][Medline] [Order article via Infotrieve]
5. Scalera F, Martens-Lobenhoffer J, Täger M, Bukowska A, Lendeckel U, Bode-Böger SM. Effect of L-arginine on asymmetric dimethylarginine (ADMA) or homocysteine-accelerated endothelial cell aging. Biochem Biophys Res Commun. 2006; 345: 1075–1082.[CrossRef][Medline] [Order article via Infotrieve]
6. Dhalla NS, Temsah RM, Netticadan T. Role of oxidative stress in cardiovascular diseases. J Hypertens. 2000; 18: 655–673.[CrossRef][Medline] [Order article via Infotrieve]
7. Cooke JP. Does ADMA cause endothelial dysfunction? Arterioscler Thromb Vasc Biol. 2000; 20: 2032–2037.
8. Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol. 2004; 15: 1983–1992.
9. Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol. 2004; 24: 1023–1030.
10. Naseem KM. The role of nitric oxide in cardiovascular diseases. Mol Aspects Med. 2005; 26: 33–65.[CrossRef][Medline] [Order article via Infotrieve]
11. Vasa M, Breitschopf K, Zeiher AM, Dimmeler S. Nitric oxide activates telomerase and delays endothelial cell senescence. Circ Res. 2000; 87: 540–542.
12. Xu D, Neville R, Finkel T. Homocysteine accelerates endothelial cell senescence. FEBS Lett. 2000; 470: 20–24.[CrossRef][Medline] [Order article via Infotrieve]
13. Battershill AJ, Scott LJ. Telmisartan: a review of its use in the management of hypertension. Drugs. 2006; 66: 51–83.[CrossRef][Medline] [Order article via Infotrieve]
14. Takaya T, Kawashima S, Shinohara M, Yamashita T, Toh R, Sasaki N, Inoue N, Hirata K, Yokoyama M. Angiotensin II type 1 receptor blocker telmisartan suppresses superoxide production and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. Atherosclerosis. 2006; 186: 402–410.[CrossRef][Medline] [Order article via Infotrieve]
15. Schmieder RE. Endothelial dysfunction: how can one intervene at the beginning of the cardiovascular continuum? J Hypertens. 2006; 24: S31–S35.
16. Takai S, Kirimura K, Jin D, Muramatsu M, Yoshikawa K, Mino Y, Miyazaki M. Significance of angiotensin II receptor blocker lipophilicities and their protective effect against vascular remodeling. Hypertens Res. 2005; 28: 593–600.[CrossRef][Medline] [Order article via Infotrieve]
17. Kajihara N, Nishida T, Boku N, Tatewaki H, Eto M, Morita S. Angiotensin II type 1 receptor antagonist protects ventricular and coronary endothelial function after 24-hour heart preservation. J Heart Lung Transplant. 2005; 24: 2211–2217.[CrossRef][Medline] [Order article via Infotrieve]
18. Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravence M, Qi N, Wang J, Avery MA, Kurtz TW. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPAR-modulating activity. Hypertension. 2004; 43: 993–1002.
19. Schupp M, Janke J, Clasen R, Unger T, Kintscher U. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor- activity. Circulation. 2004; 109: 2054–2057.
20. Hsueh WA, Bruemmer D. Peroxisome proliferation-activated receptor : Implications for cardiovascular disease. Hypertension. 2004; 43: 297–305.
21. Mehta JL, Hu B, Chen J, Li D. Pioglitazone inhibits LOX-1 expression in human coronary artery endothelial cells by reducing intracellular superoxid radical generation. Arterioscler Thromb Vasc Biol. 2003; 23: 2203–2208.
22. Polikandriotis JA, Mazzella LJ, Rupnow HL, Hart CM. Peroxisome proliferation-activated receptor ligands stimulate endothelial nitric oxide production through distint peroxisome proliferation-activated receptor -dependent mechanisms. Arterioscler Thromb Vasc Biol. 2005; 25: 1810–1816.
23. Bohnstedt KC, Karlsberg B, Wahlund LO, Jönhagen ME, Basun H, Schmidt S. Determination of isoprostanes in urine samples from Alzheimer patients using porous graphitic carbon liquid chromatography-tandem mass spectrometry. J Chromatogr B. 2003; 796: 11–19.[CrossRef]
24. Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995; 92: 9363–9367.
25. Bode-Böger SM, Scalera F, Kielstein JT, Martens-Lobenhoffer J, Breithardt G, Fobker M, Reinecke H. Symmetrical dimethylarginine: A new combined parameter for renal function and extent of coronary disease. J Am Soc Nephrol. 2006; 17: 1128–1134.
26. Cooke JP. Asymmetrical dimethylarginine. The Über marker? Circulation. 2004; 109: 1813–1819.
27. Heymes C, Silvestre JB, Llorens-Cortes C, Chevalier B, Marotte F, Levy BI, Swynghedauw B, Samuel JL. Cardiac senescence is associated with enhanced expression of angiotensin II receptor subtypes. Endocrinology. 1998; 139: 2579–2587.
28. Oudot A, Martin C, Busseuil D, Vergely C, Demaison L, Rochette L. NADPH oxidases are in part responsible for increased cardiovascular superoxide production during aging. Free Radic Biol Med. 2006; 40: 2214–2222.[CrossRef][Medline] [Order article via Infotrieve]
29. Ye P, Zhang XJ, Wang ZJ, Zhang C. Effect of aging of peroxisome proliferator-activated receptor and the possible relation to insulin resistance. Gerontology. 2006; 52: 69–75.[CrossRef][Medline]
[Order article via Infotrieve]
30. Imayama I, Ichiki T, Inanaga K, Ohtsubo H, Fukuyama K, Ono H, Hashiguchi Y, Sunagawa K. telmisartan downregulates angiotensin II type 1 receptor through activation of peroxisome proliferator-activated receptor . Cardiovasc Res. 2006; 72: 184–190.
31. Schupp M, Clemenz M, Gineste R, Witt H, Janke J, Helleboid S, hennuyer N, Ruiz P, Unger T, Staels B, Kintscher U. molecular characterization of new selective peroxisome proliferator-activated receptor modulators with angiotensin receptor blocking activity. Diabetes. 2005; 54: 3443–3452.
32. Jung KH, Chu K, Lee ST, Kim SJ, Song EC, Kim EH, Park DK, Sinn DI, Kim JM, Kim M, Roth JK. Blockade of AT1 receptor reduces apoptosis, inflammation and oxidative stress in normotensive rats with intracerebral hemorrhage. J Pharmacol Exp Ther. 2007; 322: 1051–1058.
33. Benkirame K, Viel EC, Amiri F, Schiffrin EL. Peroxisome proliferator-activated receptor regulates angiotensin II-stimulated phosphatidylinositol 3-kinase and mitogen-activated protein kinase in blood vessel in vivo. Hypertension. 2006; 47: 102–108.
34. Rueckscloss U, Qiunn MT, Holtz J, Morawietz H. Dose-dependent regulation of NAD(P)H oxidase expression by angiotensin II in human endothelial cells: Protective effect of angiotensin II type 1 receptor blockade with coronary artery disease. Arterioscler Thromb Vasc Biol. 2002; 22: 1845–1851.
35. Chalupsky K, Cai H. Endothelial dihydrofolate reductase: Critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 2005; 102: 9056–9061.
36. Yoshida T, Yamagishi S, Nakamura K, Matsui T, Imaizumi T, Takeuchi M, koga H, Ueno T, Sata M. Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation. Diabetologia. 2006; 49: 3094–3099.[CrossRef][Medline] [Order article via Infotrieve]
37. Reiss AB, Vagell ME. PPAR activity in the vessel wall: Anti-atherogenic proprieties. Curr Med Chem. 2006; 13: 3227–3238.[Medline]
[Order article via Infotrieve]
38. Yang C, Jo SH, Csernus B, Hyjek E, Liu Y, Chadburn A, Wang YL. Activation of peroxisome proliferator-activated receptor contributes to the survival of T lymphoma cells by affecting cellular metabolism. Am J Pathol. 2007; 170: 722–732.
39. Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger MC, Wang BY, Tsao PS, Kimoto M, Vallance P, Patterson AJ, Cooke JP. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation. 2003; 108: 3042–3047.
40. Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O’Hara B, Rossiter S, Anthony S, Madhani M, Selwood D, Smith C, Wojciak-Stothard B, Rudiger A, Stidwill R, McDonald NQ, Vallance P. Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med. 2007; 13: 198–203.[CrossRef][Medline] [Order article via Infotrieve]
41. Leiper JM, Santa Maria J, Chubb A, MacAllister RJ, Charles IG, Whitley GS, Vallance P. Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and hology with microbial arginine deiminases. Biochem J. 1999; 343: 209–214.[CrossRef][Medline] [Order article via Infotrieve]
42. Jones LC, Tran CTL, Leiper JM, Hingorani AD, Vallance P. Common genetic varation in a basal promotor element alters DDAH2 expression in endothelial cells. Biochem Biophys Res Commun. 2003; 310: 836–843.[CrossRef][Medline] [Order article via Infotrieve]
43. Wakino S, Hayashi K, Tatematsu S, Hasegawa K, takamatsu I, Kanda T, Homma K, Yoshioka k, Sugano N, Saruta T. Pioglitazone lowers systemic asymmetric dimethylarginine by inducing dimethylarginine dimethylaminohydrolase in rats. Hypertens Res. 2005; 28: 255–262.[CrossRef][Medline] [Order article via Infotrieve]
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