Published online before print July 12, 2007, doi: 10.1161/CIRCRESAHA.107.151852
© 2007 American Heart Association, Inc.
Molecular Medicine |
Mechanism of High Glucose–Induced Angiotensin II Production in Rat Vascular Smooth Muscle Cells
From the Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis.
Correspondence to Kafait U. Malik, PhD, DSc, Professor of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163. E-mail kmalik{at}utmem.edu
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Abstract |
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Angiotensin II (Ang II), a circulating hormone that can be synthesized locally in the vasculature, has been implicated in diabetes-associated vascular complications. This study was conducted to determine whether high glucose (HG) (
23.1 mmol/L), a diabetic-like condition, stimulates Ang II generation and the underlying mechanism of its production in rat vascular smooth muscle cells. The contribution of various enzymes involved in Ang II generation was investigated by silencing their expression with small interfering RNA in cells exposed to normal glucose (4.1 mmol/L) and HG. Angiotensin I (Ang I) was generated from angiotensinogen by cathepsin D in the presence of normal glucose or HG. Although HG did not affect the rate of angiotensinogen conversion, it decreased expression of angiotensin-converting enzyme (ACE), downregulated ACE-dependent Ang II generation, and upregulated rat vascular chymase–dependent Ang II generation. The ACE inhibitor captopril reduced Ang II levels in the media by 90% in the presence of normal glucose and 19% in HG, whereas rat vascular chymase silencing reduced Ang II production in cells exposed to HG but not normal glucose. The glucose transporter inhibitor cytochalasin B, the aldose reductase inhibitor alrestatin, and the advanced glycation end product formation inhibitor aminoguanidine attenuated HG-induced Ang II generation. HG caused a transient increase in extracellular signal-regulated kinase (ERK)1/2 phosphorylation, and ERK1/2 inhibitors reduced Ang II accumulation by HG. These data suggest that polyol pathway metabolites and AGE can stimulate rat vascular chymase activity via ERK1/2 activation and increase Ang II production. In addition, decreased Ang II degradation, which, in part, could be attributable to a decrease in angiotensin-converting enzyme 2 expression observed in HG, contributes to increased accumulation of Ang II in vascular smooth muscle cells by HG.
Key Words: ACE • vascular chymase • angiotensin • VSMC • high glucose
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Introduction |
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Angiotensin (Ang) II, a biologically active component of the renin–angiotensin system (RAS), plays an important role in regulating salt, water, and vascular homeostasis.1 According to the classical view of RAS, Ang II is cleaved from angiotensin I (Ang I) by angiotensin-converting enzyme (ACE),2 which is localized on the surface of endothelial cells but also has been shown to be present in the media of aorta and to a lesser degree in adventitia.3 A soluble form of ACE can be found in plasma.4 Ang I is formed from the circulating precursor angiotensinogen (AGT) secreted from the liver and is cleaved by renin secreted from the juxtaglomerular cells of the kidney.5
The presence of local RAS has also been demonstrated in several tissues including vascular wall.6 AGT is the only known precursor of Ang I and Ang II and is synthesized in vascular smooth muscle cells (VSMCs).7 Evidence for the presence of renin in vascular tissue has been documented,8 but renin-like activity in aortic tissue falls to very low levels after nephrectomy.9 Renin-like activity has also been shown for cathepsin D.10
Several enzymes with serine protease activity that convert Ang I to Ang II have been found in blood vessels and VSMCs. In human carotid artery atheroma, cathepsin G has been proposed to be the major Ang II–generating enzyme.11 Mast cell chymase converts Ang I to Ang II in vivo.12 Vascular chymase is a major serine protease implicated in the ACE-independent production of Ang II in human arteries.6 Elastase2, expressed in rat mesenteric arteries, is involved in Ang II production.13 Proteinase3 can also generate Ang I from AGT and Ang II from Ang I or AGT in vitro.14 Tissue plasminogen activator (tPA) directly converts AGT to Ang II in vitro.1 A new component of the RAS, ACE2, converts Ang I to Ang(1–9) and Ang II to Ang(1–7), a peptide with vasodilator and antiproliferative properties. ACE2 catalytic efficiency is 400-fold higher for Ang II(1–8) as a substrate than for Ang I(1–10).15
Prolonged hyperglycemia activates polyol pathway16 and promotes deposition of advanced glycation end products (AGEs) that are formed from nonenzymatic glycation of proteins and lipids after contact with reducing sugars.17 AGEs play an important role in the development and progression of vascular injury in diabetes-associated atherosclerosis,18 whereas chemical degradation of AGEs or inhibition of AGEs formation decreases both micro- and macrovascular complications in animal models.16,19 Ang II infusion in the rat increases serum and renal levels of AGEs. ACE inhibitors and Ang II type 1 receptor blockers reduce AGEs accumulation and delay onset of vascular complications in diabetes.20,21 Ang II stimulates glucose transport in VSMCs22 via glucose transporter GLUT1.23 High glucose (HG) promotes VSMC proliferation by activating protein kinase Cß and NADPH oxidase,16,24,25 a mechanism also shared by Ang II.25 Although VSMCs are capable of synthesizing Ang II,7 the exact pathway for its production in these cells has not yet been established. HG increases Ang II formation in rat cardiomyocytes26 and mesangial cells,25 and AGEs increase Ang II formation in human VSMCs.7 However, it is not known whether HG stimulates Ang II generation in VSMCs. Because hyperglycemia is a direct link to AGE formation,17 it raises the possibility that HG (diabetes-like condition) might stimulate Ang II formation by activating one or more components of RAS in rat VSMCs. To test this hypothesis, we examined the participation of genes involved in endogenous Ang II formation by silencing their expression with small interfering (si)RNAs and by treatment with inhibitors. Degradation of exogenous Ang II by VSMCs was also examined.
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Materials and Methods |
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Experimental Protocol
We replaced 50% of the media every 12 hours to maintain a glucose concentration of
4.1 mmol/L (normal glucose [NG]) and 23.1 mmol/L (HG). After treatments with inhibitors or siRNA, cells were harvested for mRNA or protein extraction at different time points. An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournals.org. |
Results |
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Effect of HG on Ang I and Ang II Levels in VSMCs and the Media
Exposure of VSMCs to HG did not affect Ang I levels in cells (Figure 1A) but decreased Ang I concentration in the media at 72 hours (Figure 1C). On the other hand, HG treatment increased Ang II levels in cells and media. In cells, Ang II concentration was elevated at 72 hours by more than 2.5-fold and more than 1.5-fold in the media (Figure 1B and 1D). In VSMCs exposed to NG, Ang I level was 4-fold higher than that of Ang II, but in media, Ang II abundance was 5-fold higher than that of Ang I (Figure 1A and 1B). HG treatment decreased the Ang I/Ang II ratio in cells from 4.35 to 1.97 and increased that of the Ang II/Ang I ratio in the media from 5.44 to 26.6 (Figure 1C and 1D). To exclude the osmolar effect on Ang II formation, we used 20.0 mmol/L mannitol or 15.0 mmol/L D-glucose with 5.0 mmol/L 2-DO-glucose treatment (supplemental Figure I).
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Effect of HG on ACE mRNA Expression, Protein Level, and ACE Activity
HG initially upregulated ACE mRNA expression, but after 24 hours, it decreased by more than 2.5-fold (Figure 2A). HG also downregulated ACE protein level and ACE activity in cells; this decrease was observed at 24 hours, whereas the ACE mRNA level was slightly elevated (Figure 2A and 2B). Thereafter, ACE mRNA was also decreased by HG treatment. The concentration of ACE in the media increased by 1.7-fold after 2 hours followed by a decrease at 48 hours to a level lower than that observed for NG (Figure 2C). ACE activity in the media of cells exposed to HG followed the same pattern as protein levels, suggesting that HG does not affect the activity of secreted enzyme (Figure 2D). The ratio of ACE protein levels in the media and cells reflects the rate of ACE shedding. HG increased ACE shedding with a peak at 24 hours (Figure 2E). Thereby explaining why the ACE protein level in cells was decreased when mRNA expression was not altered. After 24 hours, the rate of ACE shedding was similar to that observed for NG, despite the fact that ACE concentration in the media was diminished (Figure 2D and 2E).
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P<0.005 vs the corresponding value in the presence of NG at different time points. F, Effect of captopril on Ang II levels in cell lysate (mean±SEM, n=3). G, Effect of captopril on Ang II levels in cultured media (mean±SEM, n=3). *P<0.05 and #P<0.01 vs vehicle in the presence of NG.Under NG, ACE inhibitor, captopril, decreased Ang II concentration in the media by 8.92-fold and only by 1.22-fold in presence of HG (Figure 2G). Captopril treatment had no effect on Ang II abundance in cell lysate (Figure 2F) and did not alter the levels of Ang I in the cells or in the media obtained with NG or HG (data not shown).
Expression of Cathepsin D, tPA, Chymase1, and Rat Vascular Chymase in VSMCs
To determine the contribution of various enzymes involved in Ang II generation, we examined the abundance of their mRNA and protein. Renin, cathepsin G, elastase2, and proteinase3 were not expressed (data not shown). AGT mRNA and protein were detected in cells, and HG did not alter either mRNA or protein levels of AGT (supplemental Figure IIA and IIB). Secreted AGT protein was also found in the media, and again HG did not alter its level (supplemental Figure IIC). Cathepsin D is expressed in rat VSMCs,27 and we also found its mRNA and 2 precursor proteins (52 and 45 kDa) and active enzyme (32 kDa) in cells. The active form of cathepsin D was also detected in the media. HG had no effect on cathepsin D mRNA or protein levels in cells (Figure 3A) or media (supplemental Figure IIIA). mRNA and protein levels of tPA, which can directly convert AGT to Ang II in vitro,1 increased after 48 hours of HG treatment (Figure 3B). At the same time, the level of secreted tPA in the media was not altered by HG (supplemental Figure IIIB). HG did not affect expression of chymase1 or rat vascular chymase (rVCh) (Figure 3C and 3D). Neither chymase1 nor rVCh protein was detected in the media (data not shown).
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Effect of Cathepsin D, tPA, Chymase1, and rVCh Silencing on Ang I and Ang II Formation by VSMCs
Cathepsin D siRNA, which reduced its mRNA (supplemental Figure IVA), decreased Ang I and Ang II levels both in VSMCs and the media by more than 2-fold (Figure 4). This effect of cathepsin D silencing was observed in VSMCs exposed to NG and HG. Silencing the tPA gene with its siRNA (supplemental Figure IVB) did not alter the levels of Ang I or Ang II in the cells or media during NG treatment. However, tPA silencing in VSMCs exposed to HG for 72 hours increased Ang I and Ang II levels in cells by 1.43- and 2.22-fold, respectively (Figure 4A and 4B), and decreased Ang I and Ang II levels in the media by 2.51- and 8.85-fold, respectively (Figure 4C and 4D).
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Chymase1 silencing (supplemental Figure IVC) significantly increased the Ang II level in cells after 72 hours of incubation with NG or HG compared with levels in cells treated with control siRNA (Figure 4B), but chymase1 silencing did not affect Ang I or Ang II concentration in media or Ang I abundance in cells (Figure 4A, 4C, and 4D).
Silencing of rVCh with siRNA (supplemental Figure IVD) decreased the Ang II level in cells by 16.32-fold (Figure 4B) and Ang II concentration in the media by 4.56-fold in the presence of HG compared with levels in the presence of control siRNA (Figure 4D). Although there was some decrease in Ang II concentration in media in the presence of NG, it was not significant (P>0.05) (Figure 4D). On the other hand, rVCh gene silencing increased the Ang I concentration in media but not in the cells (Figure 4A and 4B).
Effect of Cytochalasin B, Alrestatin, and Aminoguanidine on Ang I and Ang II Formation
HG slightly upregulated glucose transporter GLUT123 mRNA expression at 72 hours but not the protein level (supplemental Figure VA). GLUT4 mRNA expression was hardly detectable, and protein was absent (data not shown). Activation of the polyol pathway and aldose sugar formation by aldose reductase (AR) is the key step for the formation of AGE.17,18,28 HG elevated AR mRNA and protein levels (supplemental Figure VB). The GLUT1 blocker cytochalasin B29 (10 µmol/L), the AR inhibitor alrestatin16 (10 µmol/L), and the AGE formation inhibitor aminoguanidine17 (10 µmol/L) minimized HG-induced increase in Ang II (Figure 5B and 5D). All agents attenuated the decrease in the Ang I level in the media produced by HG (Figure 5C).
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Degradation of Exogenous Ang II by VSMCs and Effect of Extracellular Signal-Regulated Kinase 1/2, p38 MAPK Inhibitors, or Dominant-Negative p38 MAPK on Ang II Formation
Cells grown in either NG or HG for 72 hours were treated with 200 nmol/L Ang II for 4 hours. Degradation of exogenous Ang II by cells exposed to HG was notably slower. The Ang II concentration was 1.69-fold higher in the media of cells exposed to HG than to NG (Figure 6A). On the other hand, the Ang II concentration in the cells treated with exogenous Ang II for 4 hours was significantly higher in the presence of HG, whereas it was not altered in cells exposed to NG (Figure 6B).
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Hyperglycemia increases AGE formation,17 and in human VSMCs, AGEs stimulate Ang II formation by increasing vascular chymase expression by activating extracellular signal-regulated kinase (ERK)1/2, but not p38 MAPK.7 In our study, HG increased ERK1/2 phosphorylation at 4 hours and p38 MAPK at 2 hours; thereafter, phosphorylation was reduced, reaching levels below that observed in the presence of NG after 12 hours for ERK1/2 and 48 hours for p38 MAPK (Figure 6C and 6D). Therefore, we examined the effect of ERK1/2 and p38 MAPK inhibitors or dominant-negative p38 MAPK30 on Ang II levels in the media. The ERK1/2 inhibitors U0126 and PD98059, but not p38 MAPK inhibitors SB202190 and SB203580 or dominant-negative p38 MAPK, which inhibited p38 MAPK activity (supplemental Figure VI), reduced Ang II levels in the media of cells exposed to HG (Figure 6E). Wild-type p38 MAPK increased Ang II levels in presence of NG.
Effect of HG on ACE2 mRNA and Protein Levels
The pattern of ACE2 mRNA expression was similar to that observed for ACE. Initially, HG treatment elevated the ACE2 mRNA level by 1.71-fold. However, after 12 hours, ACE2 mRNA expression was downregulated and at 72 hours, ACE2 mRNA was 8.07-fold lower compared with that observed in the presence of NG (Figure 7A). In addition, HG reduced the ACE2 protein level in cells by 1.75-fold at 72 hours (Figure 7B). HG also increased ACE2 protein shedding (data not shown).
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Discussion |
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This study demonstrates that in rat VSMCs, both Ang I and Ang II are generated in the presence of NG. Exposure to HG increased Ang II but not Ang I levels in the cells at 48 hours as well as in the cultured media at 24 hours. To determine the pathway of Ang II generation in VSMCs and the mechanism by which HG increases Ang II levels, we examined the contribution of several enzymes known to generate Ang II in vascular tissues.11–13 The summary of the proposed pathway for Ang I and Ang II formation is presented in Figure 8. We did not detect renin mRNA in rat VSMCs, but cathepsin D, which can generate Ang I from AGT,10 was highly expressed. HG did not alter cathepsin D mRNA or protein levels. Our observation that silencing of cathepsin D by 72.8% decreased Ang I levels in the cells and media to a similar degree in presence of NG or HG confirms that cathepsin D is the main enzyme that cleaves Ang I from AGT, and increased generation of Ang II in presence of HG is unlikely to be attributable to alteration in cathepsin D activity. Because AGT and cathepsin D were found in the media, extracellular formation of Ang I is also possible. However, optimal pH for cathepsin D on AGT as substrate is 5.5, which is more likely to exist in lysosome than in cultured media.10 Although AGT and cathepsin D levels were similar in the culture media of cells exposed to NG and HG, Ang I level in the media was reduced after 48 hours in the presence of HG. Therefore, it appears that Ang I formation in NG and HG is similar but the cleavage of Ang I to Ang II is mediated through a different pathway.
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It has been proposed that tPA converts AGT directly to Ang II.1 In the presence of NG, tPA silencing did not alter Ang I or Ang II levels either in the cells or culture media. However, in cells exposed to HG, tPA silencing increased intracellular accumulation of Ang I and Ang II, which was associated with an appropriate decrease in Ang I and Ang II levels in media (Figure 4). Because the effect of HG on Ang I and Ang II levels was associated with increased tPA expression, we propose that tPA could be involved in Ang I and Ang II transport out of the cells rather than in Ang II synthesis. From these observations, it follows that HG increases Ang II production. Therefore, we examined the contribution of enzymes that are capable of converting Ang I to Ang II in VSMCs.
Although the ACE-dependent Ang II generation prevails in rat VSMCs exposed to NG, HG diminishes the contribution of ACE. Despite the fact that HG temporarily elevated ACE expression in VSMCs, ACE protein level and activity after 24 hours of HG treatment were significantly reduced in the cells and media. Our finding further supported that in the presence of NG, captopril decreased the Ang II level in media by more than 90% and less than 19% in the presence of HG without altering the Ang II level in cells (Figure 2). Similarly, ACE expression is downregulated in animal models of diabetic kidneys.31,32
Another enzyme implicated in the conversion of Ang I to Ang II is chymase.7,33 However, previously published data on the contribution of chymostatin-inhibitable Ang II generation in vascular tissues are controversial. All mammalian chymases represent 2 distinct isoenzyme groups, 
and ß. -Chymases include human chymase, dog chymase, and rat chymase3. ß-Chymases include rat chymase1 and -2, and mouse chymase1, -2, and -4.34 Kinetic studies indicate that - and ß-chymases differ in their substrate specificity. Thus, -chymase cleaves Ang I at the Phe8
bond with a 750-fold higher catalytic efficiency than the Tyr4 bond in Ang II, whereas rat chymase1 cleaves the Tyr4 bond with a 20-fold higher catalytic efficiency than the Phe8 bond.35 It has been reported that in the extract from rat vascular tissues, Ang II formation is suppressed to 4% by lisinopril but not by chymostatin.36 Our results suggest that chymase1, which is a ß-chymase, is involved in Ang I and/or Ang II degradation rather than Ang II synthesis, because chymase1 silencing increased Ang II abundance in cells in the presence of NG and HG (Figure 4B). Alternatively, mouse cell protease-4, identified as a ß-chymase, has been shown to promote Ang II generation,37 and chymase-like Ang II–forming activity was predominant in rat heart and aorta.38 Moreover, novel rVCh shows increased chymostatin-inhibitable Ang I converting activity in hypertensive rats.33 Indeed, in our study, rVCh silencing in the presence of HG significantly reduced Ang II abundance in cells and media. Because captopril caused less than a 19% decrease in Ang II abundance, rVCh is most likely the main Ang II–forming enzyme in the presence of HG. Silencing of rVCh was associated with an increase in Ang I level in the media, which is most likely attributable to increased Ang I transport outside the cell as a result of a decreased rate of Ang I conversion in cytosol. Because HG did not affect rVCh mRNA or protein abundance, we propose that higher Ang II–forming activity of this enzyme could involve posttranslational modification. It is possible that rVCh is similar to mast cell chymase, which is stored in secretory granules as an inactive proenzyme to be activated.39 Thus, in A10 cells rVCh is translated initially as a zymogen and then processed to an active form by endogenous dipeptidyl peptidase I.33 Also formation of complex of chymase with heparin proteoglycan could potentiate its catalytic activity in the presence of HG.40 Thus, activation of chymase-dependent Ang II formation in injured vessels,41 hypertensive rats,33 and ischemic heart42 has been proposed as a sign of tissue damage.
The mechanism by which HG promotes Ang II generation by VSMCs is not known. Recently it has been reported that AGEs through their receptor (RAGE) could stimulate chymase-dependent Ang II generation via ERK1/2 activation in VSMCs.7 Therefore, it is possible that excessive glucose uptake can stimulate production of reducing sugars by AR, leading to AGE accumulation, which in turn stimulates Ang II production. Supporting this view, we demonstrated that the GLUT1 inhibitor cytochalasin B, AR inhibitor alrestatin, and AGE formation inhibitor aminoguanidine attenuated the effect of HG to increase Ang II accumulation in cells and media and decrease the Ang I level in media (Figure 5). The partial inhibitory effect of alrestatin could be attributable to posttranscriptional modification of AR such as S-thiolation, which makes this enzyme less sensitive to inhibitors.43 Our finding that HG increased ERK1/2 and p38 MAPK phosphorylation and that the inhibitors of ERK1/2 but not the inhibitors of p38 MAPK or dominant-negative p38 MAPK minimized a HG-induced increase in Ang II levels suggests that HG or AGEs via ERK1/2, but not p38 MAPK, activation could increase rVCh activity and Ang II generation. However, ERK1/2 activation either by HG or by AGEs7 was transient. HG increased phosphorylation of ERK1/2 at 4 hours, and thereafter it declined, reaching the basal level at 12 hours and below basal level after 24 hours (Figure 6C). It is possible that ERK1/2 phosphorylation is required only as an initial step for rVCh-dependent Ang II formation. However, we cannot exclude any nonspecific effect of ERK1/2 inhibitors.
In view of our observations that HG did not alter either AGT or cathepsin D mRNA, protein abundance, or cell levels of Ang I, it appears that in cell lysates, Ang I accumulation reflects the steady rate of AGT conversion to Ang I. Because Ang I is the only substrate for ACE or rVCh to generate Ang II, Ang I abundance would be the limiting factor for Ang II formation. On the other hand, the balance between Ang II generation and degradation could play a significant role in maintaining a steady-state level of Ang II. Thus, HG decreases exogenous Ang II degradation when cells were exposed to HG for 72 hours. In addition, there was increased Ang II accumulation in the cells compared with that observed in VSMCs exposed to NG. Because HG also decreased mRNA expression and protein level of ACE2, which can convert Ang II into Ang(1–7) it is possible that downregulation of ACE2 expression may contribute to increased levels of Ang II generated in the presence of HG. In fact, in ACE2-knockout mice, circulating Ang II levels were elevated44 and ACE and ACE2 mRNA expression was decreased by approximately 50% in kidneys from diabetic Sprague–Dawley rats.31 HG may also affect Ang II degradation by angiotensinases45 or decrease its conversion to Ang III and Ang IV.46 Moreover, Ang I could be converted to Ang(1–7) by neprilysin in the heart and kidney.47,48
In conclusion, this study shows for the first time that in rat VSMCs exposed to HG, Ang I to Ang II conversion by ACE switches from the classic pathway to rVCh, ie, from an extracellular (physiological) to an intracellular (pathological) site of Ang II production. In addition, HG minimizes Ang II degradation. Activation of rVCh by HG is probably mediated via ERK1/2 by glucose metabolites generated through the polyol pathway and that of AGE. Because AGT and Ang II can be delivered to the vasculature from the blood stream, decreased Ang II degradation, in addition to local production by rVCh in VSMCs, might contribute to the vasculopathy associated with hyperglycemia, and inhibitors of vascular chymase might be useful in preventing diabetic vascular complications.
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Acknowledgments |
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We thank Dr F. A. Yaghini for substantial technical assistance during manuscript preparation, Dr D. L. Armbruster for editorial suggestions, and Dr G. A. Cook for help with quantitative RT-PCR.
Sources of Funding
This work was supported by NIH National Heart, Lung and Blood Institute grant 19134-32.
Disclosures
None.
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Footnotes |
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Original received March 12, 2007; revision received June 27, 2007; accepted July 3, 2007.
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