Published online before print March 9, 2009, doi: 10.1161/HYPERTENSIONAHA.108.118919
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(Hypertension. 2009;53:682.)
© 2009 American Heart Association, Inc.
Original Articles |
Vascular-Protective Effects of High-Density Lipoprotein Include the Downregulation of the Angiotensin II Type 1 Receptor
From the Department of Cardiology and Pneumology (S.V.L., F.S., M.M., M.E., H.-P.S., C.T.), Charité–University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany; Department of Cardiology and Angiology (M.L., V.S.), Charité–University Medicine Berlin, Campus Mitte, Berlin, Germany; and the Center for Molecular and Vascular Biology (F.J., B.D.G.), University of Leuven, Leuven, Belgium.
Correspondence to Carsten Tschöpe, Department of Cardiology and Pneumology, Charité–University Medicine of Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail carsten.tschoepe{at}charite.de
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Abstract |
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There is growing evidence that a cross-talk exists between the renin-angiotensin (Ang) system and lipoproteins. We investigated the role of high-density lipoprotein (HDL) on Ang II type 1 receptor (AT1R) regulation and subsequent Ang II–mediated signaling under diabetic conditions. To investigate the effect of HDL on AT1R expression in vivo, apolipoprotein A-I gene transfer was performed 5 days after streptozotocin injection. Six weeks after apolipoprotein A-I gene transfer, the 1.9-fold (P=0.001) increase of HDL cholesterol was associated with a 4.7-fold (P<0.05) reduction in diabetes mellitus–induced aortic AT1R expression. Concomitantly, NAD(P)H oxidase activity, Nox 4, and p22phox mRNA expression were reduced 2.6-fold, 2.0-fold, and 1.5-fold (P<0.05), respectively, whereas endothelial NO synthase dimerization was increased 3.3-fold (P<0.005). Apolipoprotein A-I transfer improved NO bioavailability as indicated by ameliorated acetylcholine-dependent vasodilation in the streptozotocin-Ad.hapoA-I group compared with streptozotocin-induced diabetes mellitus. In vitro, HDL reduced the hyperglycemia-induced upregulation of the AT1R in human aortic endothelial cells. This was associated with a 1.3-fold and 2.2-fold decreases in reactive oxygen species and NAD(P)H oxidase activity, respectively (P<0.05). Finally, HDL reduced the responsiveness to Ang II, as indicated by decreased oxidative stress in the hyperglycemia+HDL+Ang II group compared with the hyperglycemia+Ang II group. In conclusion, vascular-protective effects of HDL include the downregulation of the AT1R.
Key Words: high-density lipoprotein • angiotensin AT1 receptor • endothelial function • diabetes mellitus
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Introduction |
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Diabetes mellitus is associated with endothelial dysfunction, an early phase of atherosclerosis further characterized by a reduction in NO bioavailability, without significant morphological changes of the vessel wall.1,2 Both diabetes mellitus–associated hyperglycemia and increased angiotensin (Ang) II levels3 induce reactive oxygen species (ROS), which contribute to endothelial dysfunction, partly via oxidative degradation of NO. Recent studies have demonstrated that ROS are predominantly produced by vascular NAD(P)H oxidase (NOX),4 whereas "uncoupled" endothelial NO synthase (eNOS; when eNOS produces O2·– rather then NO) is another important source of ROS in diseased, including diabetic, blood vessels.5 Numerous studies have shown that activation of the Ang II type 1 receptor (AT1R) contributes to the induction of oxidative stress and apoptosis of vascular cells, thus contributing to the initiation and progression of endothelial dysfunction.6 Ang II not only increases NOX activity but also uncouples eNOS in diabetic mice.7 The expression levels of the AT1R define the biological efficacy of Ang II and have been shown to be regulated by several agonists, such as Ang II, glucose, insulin, ROS, low-density lipoprotein (LDL), and many others,8,9 including diabetes mellitus.10,11 The importance of the enhanced vascular AT1R expression and Ang II–mediated signaling in diabetes mellitus–associated endothelial dysfunction follows from the finding that AT1R antagonism in diabetes mellitus improves endothelial function.7,12
The vascular protective effects of high-density lipoprotein (HDL) are well documented: low plasma HDL is an independent predictor of endothelial dysfunction in healthy individuals and diabetic patients,13,14 and elevation of plasma HDL by drug treatment with niacin or by infusion of synthetic HDL leads to a significant improvement of impaired endothelial function.15 Recently, HDL-mediated reduction in NOX activity has been demonstrated.16
There is growing evidence that there exists a cross-talk between the renin-Ang system and lipoproteins: (1) AT1R expression is increased by LDL8 and oxidized LDL17 in vascular smooth muscle cells and human aortic endothelial cells (HAECs), respectively; (2) Ang II facilitates the oxidation of LDL and its uptake by scavenger receptors on monocytes/macrophages,18 whereas it inhibits macrophage expression of the ATP-binding cassette transporter A1,19 which regulates the transport of cholesterol and phospholipids to apolipoprotein (apo) A-I, the major apo of HDL; and (3) AT1R blockade reduces LDL cholesterol and increases HDL cholesterol in diabetic patients.20
We hypothesized that the vascular-protective effects of HDL may include the downregulation of the AT1R and thereby reduce Ang II–mediated signaling. To further explore this hypothesis, we investigated the influence of HDL on AT1R regulation in vivo in an experimental model of diabetes mellitus–induced endothelial dysfunction and in vitro in HAECs under hyperglycemia (HG) in the presence or absence of Ang II.
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Methods |
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For detailed methodology, please see the data supplement (available online at http://hyper.ahajournals.org). In brief, diabetes mellitus was induced by a single injection of streptozotocin (STZ; 70 mg/kg; IP) in 8-week-old male Sprague-Dawley (SD) rats. Five days after STZ injection, IV gene transfer with 3x1012 particles per kg of the E1E3E4-deleted adenoviral vector Ad.hapo A-I, which induces hepatocyte-specific expression of human apo A-I in the absence of significant hepatotoxicity,21 or of the control vector Ad.Null, which contains no expression cassette,21 was performed. Six weeks after gene transfer, rats were euthanized, and endothelium-dependent vasorelaxation was determined. Aorta was snap frozen for subsequent rat AT1R, Nox 1, Nox 2 (gp91phox), Nox 4, p22phox and extracellular (ec)-superoxide dismutase (SOD) mRNA expression, eNOS protein level, eNOS dimerization, NAD(P)H oxidase, and SOD activity analysis. In vitro, the effects of HDL on AT1R mRNA and eNOS protein expression and Ang II responsiveness in HAEC were determined.
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Results |
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Human Apo A-I Gene Transfer in STZ-Induced Diabetic Rats
Ad.hapoA-I gene transfer resulted in persistent hepatocyte-specific expression of human apo A-I for the entire duration of the experiment, 6 weeks, leading to 1.9-fold (P=0.001) increased levels of HDL cholesterol at the day of sacrifice compared with STZ-Ad.Null rats. Human apo A-I transfer did not result in significant changes of blood glucose concentrations or in alterations of LDL cholesterol levels (supplemental Figure S1A through S1D).
Human apo A-I gene transfer reduces AT1R expression in the diabetic aorta, and supplementation of HDL reduces HG-induced AT1R expression in HAECs. Aortic AT1R expression was 4.7-fold (P<0.05) increased in STZ-induced diabetic rats compared with SD-Ad.Null rats. Ad.hapoA-I gene transfer normalized AT1R expression in STZ-induced diabetic rats to levels found in SD-Ad.Null rats (Figure 1A). The AT1R mRNA expression was 4.6-fold (P<0.0005) increased in HAECs under HG. HDL supplementation reduced AT1R mRNA expression in a dose-dependent manner, reaching AT1R mRNA levels of controls at 50 µg/mL (25 µg/mL: P value not significant; 37.5 µg/mL: 2.2-fold [P<0.05]; 50 µg/mL: 3.6-fold [P<0.01]; and 100 µg/mL: 2.6-fold [P<0.05] lower versus HG, respectively; Figure 1B). Under normoglycemic conditions, HDL had no significant effect on AT1R mRNA expression with the exception of 2.5-fold–lower (P<0.05) expression levels at an HDL concentration of 25 µg/mL (Figure 1B).
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P<0.05 vs HG.
Human Apo A-I Gene Transfer Reduces NAD(P)H Oxidase Activity in the Diabetic Aorta
Nox 1 and Nox 2 mRNA expressions were not significantly induced under diabetic conditions. Human apo A-I gene transfer resulted in a 2.0-fold and 1.5-fold (P<0.05) reduction of diabetes mellitus–upregulated aortic Nox 4 and p22phox mRNA expression, respectively, and decreased the diabetes mellitus–induced NOX activity by 2.6-fold (P<0.05). In STZ-induced diabetic rats, mRNA expression of the antioxidative ec-SOD was 1.6-fold (P<0.05) increased after apo A-I gene transfer, whereas the diabetes mellitus–induced SOD activity was 3.5-fold (P<0.05) decreased. (Figure 2A through 2D).
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HDL Reduces the Responsiveness to Ang II in HAECs Under HG
HG induced 2'-7'-dichloro-dihydrofluorescein fluorescence and NOX activity by 1.3-fold and 2.2-fold, respectively (P<0.005), which was significantly reduced after HDL supplementation. The oxidative stress response toward Ang II was most pronounced under hyperglycemic conditions (Figure 3A and 3B).
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, basal; 
, in the presence of 1 µmol/L Ang II. *P<0.005 vs C and HG+HDL; 
P<0.05 vs HG;
Human Apo A-I Gene Transfer Restores eNOS Dimerization in the Diabetic Aorta
Total eNOS levels increased 2.5-fold (P<0.05) in STZ-induced diabetic rats relative to controls, whereas apo A-I gene transfer reduced diabetes mellitus–induced eNOS toward levels not significantly different from SD-Ad.Null (Figure 4A). In contrast, the ratio of eNOS dimer:monomer in STZ-induced diabetic rats was 3.0-fold (P<0.005) lower compared with that in SD-Ad.Null, as assayed by low temperature SDS-PAGE and immunoblotting. Apo A-I gene transfer increased the eNOS dimer:monomer ratio by 3.3-fold (P<0.005) versus the STZ-induced diabetic group, leading to ratios not significantly different from SD-Ad.Null (Figure 4B). In vitro, under HG, eNOS expression was 1.7-fold (P<0.05) increased and normalized to normoglycemic control levels in the presence of HDL in HAECs (Figure 4C).
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Vascular Reactivity Is Improved After Human Apo A-I Gene Transfer
To evaluate whether NO bioavailability was increased in vivo as a consequence of reduced NOX activity, restored SOD activity, and enhanced eNOS coupling, endothelium-dependent relaxation was evaluated in vivo. Acetylcholine-induced endothelium-dependent relaxation was significantly impaired in aortic rings of STZ-induced diabetic rats compared with SD-Ad.Null (P<0.05). Endothelium-dependent vasorelaxation was not significantly different in STZ-induced diabetic rats injected with Ad.Null (n=24) or saline (n=20). Therefore, both control diabetic groups were pooled in SD-STZ. Apo A-I gene transfer significantly improved vascular reactivity to acetylcholine in STZ-induced diabetic rats to control levels (P<0.05; Figure S2A). Endothelium-independent papaverine-induced relaxations were not different among all of the groups (Figure S2B).
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Discussion |
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Our study reveals the downregulation of the AT1R as a novel vascular-protective mechanism of HDL, as demonstrated in vivo in the aorta of STZ-induced diabetic rats and in vitro in HAECs. We postulated that the reduction in aortic AT1R expression after apo A-I transfer is a significant mediator of subsequent reduced NOX activity and reduced eNOS uncoupling leading to improved endothelial function in experimental diabetes mellitus.
Under diabetic conditions, the renin-Ang system is activated and vascular AT1R expression is enhanced,11,22 thereby contributing to diabetes mellitus–associated endothelial dysfunction.12 Given the known vascular (endothelial)-protective effects of HDL,13–15 we hypothesized that HDL could also regulate vascular AT1R expression under diabetic conditions and could thereby influence Ang II–mediated signaling. To investigate this hypothesis, we increased HDL in vivo via human apo A-I gene transfer, leading to hepatocyte-specific human apo A-I expression in STZ-induced diabetic rats and supplemented HDL to HAECs under HG in the presence or absence of Ang II. In vivo, we chose a gene transfer strategy, because currently available drugs, such as fibrates, nicotinacids, and statins, only moderately and not exclusively increase HDL.23 The STZ-induced diabetes mellitus model is characterized by severe HG and is, in contrast to other diabetic animal models, not associated with reduced HDL levels.24,25 Apo A-I gene transfer did not affect glucose or LDL cholesterol levels, 2 factors known to influence AT1R expression and reduced aortic AT1R mRNA in STZ-induced diabetic rats to levels similar to nondiabetic controls. In addition, a dose-dependent effect of HDL in attenuating HG-induced elevated AT1R expression was observed. Under normoglycemic conditions, downregulation of physiological AT1R expression was only observed at 25 µg/mL, the lowest investigated dose, indicating a narrow concentration window in which HDL has an effect on AT1R expression under nonpathological conditions.
Because the expression levels of the AT1R define the biological efficacy of Ang II, HDL-mediated downregulation of the AT1R observed in the aorta of STZ-induced diabetic rats and in HAECs under HG reduces subsequent Ang II–mediated signaling. Consistent with the previously demonstrated role of the AT1R in mediating increased NOX activity and eNOS uncoupling in diabetes mellitus,7 reduction of AT1R by increased HDL cholesterol is likely the predominant mediator of decreased expression of the NOX components p22phox and Nox 4, reduced NOX activity, and decreased eNOS uncoupling in vivo. This is further corroborated by the in vitro experiments in the current study. Here, the HDL-mediated downregulation of the AT1R in HAECs was associated with a decrease in HG-induced oxidative stress, indicated by reduced 2'-7'-dichloro-dihydrofluorescein fluorescence and reduced NOX activity. In addition, the responsiveness to Ang II was directly evaluated. In agreement with reduced AT1R expression levels, HDL decreased the HG-induced response to Ang II, as indicated by significantly lower 2'-7'-dichloro-dihydrofluorescein fluorescence and NOX activity in the HG+HDL+Ang II group compared with the HG+Ang II group. Our finding that HDL reduces AT1R expression and subsequent Ang II–mediated signaling supports the recent observation of Tölle et al,16 who demonstrated that HDL decreases NOX-dependent ROS generation via inhibition of the activation of Rac1, which is a downstream AT1R-dependent mediator of Ang II.26
We suggest that reduced peroxynitrite formation as a result of lower NOX activity,27 after apo A-I transfer, decreased eNOS uncoupling and improved NO bioavailability, as evidenced by improved endothelial function. In addition, the increased eNOS dimer:monomer ratio, as a consequence of reduced NOX activity,28 may also have contributed to enhanced NO bioavailability, because oxygen reduction is always uncoupled from NO formation in monomers. Increased eNOS expression under HG or diabetes mellitus5,29–31 has been considered to represent a feedback response to reduced NO bioavailability.32 Apo A-I transfer in STZ-induced diabetes mellitus and HDL supplementation to HAECs under HG decreased the diabetes mellitus– or HG-induced eNOS expression, suggesting that this feedback mechanism was reversed by increased NO bioavailability induced by increased HDL cholesterol.
The exact mechanism by which HDL affects AT1R regulation under diabetes mellitus requires further fundamental studies. Because oxidized LDL17 and ROS33 play a role in the induction of the AT1R in HAECs, it is tentative to postulate that HDL via intrinsic antioxidative features may contribute to the downregulation of the AT1R under diabetes mellitus, which results in less NOX activity and ROS formation, and, in turn, may reduce AT1R expression (see Figure 5). We demonstrated previously that apo A-I transfer in STZ-induced diabetic rats reduced systemic oxidative stress, as indicated by decreased plasma thiobarbituric acid reactive substances.34 This effect is likely mediated by an increase in activity of paraoxonase or platelet activating factor-acetylhydrolase, 2 enzymes with antioxidative features, associated with HDL, and known to be increased after apo A-I gene transfer.35 However, the recent finding that sphingosine-1-phosphate and sphingosylphosphorylcholine, 2 lipid components of HDL without antioxidative properties, mimicked the capacity of HDL to reduce ROS generation16 suggests that other intrinsic features of HDL may contribute to the downregulation of the AT1R.
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In conclusion, we define the downregulation of the AT1R as a novel additional vascular protective effect of HDL. We thereby further strengthen the existence of a cross-link between HDL and the renin-Ang system.
Perspectives
We demonstrated in vivo and in vitro in HAECs HDL-mediated downregulation of the AT1R, which took place in combination with reduced NOX activity and improved NO bioavailability and resulted in improved endothelial function. The STZ model allowed us to investigate the effect of an increase of HDL on AT1R regulation, independent of alterations in glucose and LDL cholesterol levels. On the other hand, we have to take into account that the characteristic lipid profile and severe HG of the STZ model disable a direct translation of our findings to type II diabetic animal models and diabetic patients.
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Acknowledgments |
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We thank Thomas Düsterhöft for excellent technical assistance.
Sources of Funding
This study was supported by the European Foundation for the Study of Diabetes to C.T. and S.V.L., the GRK 865 (Vaskuläre Regulations-mechanismen) to C.T., M.M., and V.S., and a "Nachwuchsförderungsstipendium" of the Charité to S.V.L. The Center for Molecular and Vascular Biology (B.D.G. and F.J.) is supported by the Excellentiefinanciering KU Leuven (EF/05/013). F.J. is a Research Assistant of the Instituut voor de Aanmoediging van Innovatie en Technologie in Vlaanderen.
Disclosures
None.
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Footnotes |
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S.V.L. and F.S. contributed equally to this work.
Received July 2, 2008; first decision July 23, 2008; accepted November 6, 2008.
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