This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nickenig, G. Articles by Böhm, M. Search for Related Content PubMed PubMed Citation Articles by Nickenig, G. Articles by Böhm, M. Related Collections Lipids Cardiovascular Pharmacology ACE/Angiotension receptors Other hypertension

(Circulation. 1999;100:2131.)
© 1999 American Heart Association, Inc.

Brief Rapid Communications

Statin-Sensitive Dysregulated AT1 Receptor Function and Density in Hypercholesterolemic Men

Georg Nickenig, MD¹; Anselm T. Bäumer, MD¹; Yavuz Temur, MS; Daniela Kebben, MS; Friedrich Jockenhövel, MD; Michael Böhm, MD

From the Klinik III für Innere Medizin and Klinik II für Innere Medizin (F.J.),Universität Köln, Germany.

Correspondence to Dr Georg Nickenig, Klinik III für Innere Medizin, Universität zu Köln, Joseph-Stelzmann-Str 9 50924 Köln. E-mail georg.nickenig{at}uni-koeln.de

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background—Hypercholesterolemia causes an upregulation of vascular angiotensin II type 1 (AT1) receptor expression in cell culture and animal models. The presented studies were undertaken to examine AT1 receptor overexpression in hypercholesterolemic men and therapeutic interventions thereof by HMG CoA reductase inhibitors (statins).

Methods and Results—Effects of AT1 receptor activation were measured by assessing the blood pressure increase after infusion of angiotensin II in normo- (cholesterol 181±11 mg/dL) and hypercholesterolemic (cholesterol 294±10 mg/dL) men (n=19 and 20, respectively). AT1 receptor expression was assessed on isolated platelets. Some patients were investigated before and after cholesterol-lowering therapy with statins. Hypercholesterolemia led to a significant increase of angiotensin II-induced blood pressure elevation. AT1 receptor expression was significantly enhanced in hypercholesterolemic individuals (B_max=5.2±1.2 fmol/mg protein) compared with normocholesterolemic men (B_max=2.1±0.2 fmol/mg protein). Cholesterol-lowering treatment with statins reversed the elevated blood pressure response to angiotensin II infusion (P<0.05) and downregulated AT1 receptor density (P<0.05).

Conclusions—Hypercholesterolemia induces AT1 receptor overexpression and enhances biological effects of angiotensin II in men. These findings provide novel insights into the pathogenesis of hypertension and atherosclerosis and may initiate rational and new therapeutic concepts.

Key Words: lipids • hypertension • angiotensin • receptors • atherosclerosis

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Hypercholesterolemia is a major risk factor for coronary heart disease.¹ Several cholesterol-lowering interventions have reduced cardiovascular events in secondary and primary prevention trials.^{2 3} Hypercholesterolemia is frequently associated with hypertension, another potent cardiovascular risk factor.⁴ It is thought that interactions of lipoproteins with other neurohumoral systems may play an important role.⁵ The renin-angiotensin system and especially the angiotensin II type 1 (AT1) receptor have been implicated in cardiovascular pathophysiology.⁶ Previous studies have shown that low-density lipoprotein (LDL) induces AT1 receptor upregulation in isolated vascular smooth muscle cells (VSMC) and that hypercholesterolemic rabbits display an enhanced vascular expression of AT1 receptors.^{7 8} These interactions could explain the association of hypercholesterolemia with hypertension and atherosclerosis, because AT1 receptor overexpression may account for enhanced release of free radicals and increased vasoconstriction and cell proliferation. The present study was designed to evaluate whether hypercholesterolemia causes enhanced AT1 receptor density and function in men and whether these potential alterations could be modulated by treatment with statins.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patients
Male hypercholesterolemic individuals were compared with normocholesterolemic volunteers. The exclusion criteria included any cardiovascular disease or any severe disease of other origin at present or in the past, any cardiovascular medication, any long-term medical treatment, lipid-lowering drugs, history of drug or alcohol abuse, and current treatment with any investigational drug. Patients gave written consent, and a physical examination, an ECG, and blood pressure were taken. Fasting serum cholesterol and triglycerides measurements were performed. The study was approved by the ethics committees of the University of Cologne.

Blood Pressure
Basal blood pressure was evaluated after 30 minutes resting time in supine position. 0.5 to 20 ng · kg^-1 · min^-1 of angiotensin II was infused stepwise via cubital vein (6 minutes per concentration). Blood pressure was automatically assessed in 2-minute intervals. Thirty minutes later, the norepinephrine infusion was started (0.6 to 4.8 µg · kg^-1 · min^-1). Drug administration was ceased after reaching 190 mm Hg systolic or 110 mm Hg diastolic blood pressure, occurrence of chest pain, or arrhythmias.

Radioligand Binding Assays
Blood (60 mL) was drawn and stored on ice. Platelet-rich supernatant was collected and centrifuged (4°C for 10 minutes) at 1313g. The platelet pellet was resuspended and washed twice. Platelets were incubated with increasing concentrations of ¹²⁵I-angiotensin II (0.2 to 2 nmol/L). Nonspecific binding was assessed in the presence of 10 µmol/L losartan. Incubation was performed for 60 minutes at room temperature. Reaction were terminated by aspiration with ice-cold buffer containing 0.5% BSA and 10 mmol/L Tris-HCl through GF/C Whatman filters with a Brandel cell harvester.

Statistics
All results are given as mean±SEM. Statistical procedures were performed using SSPS 7.0 software. For comparisons, nonparametric tests (Mann-Whitney U test, Wilcoxon test) were applied. Correlations were calculated using the Pearson test.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Detailed characteristics of the enrolled patients are given in Table 1. Men with cholesterol plasma levels 200 mg/dL and LDL concentrations 130 mg/dL were included into the normocholesterolemic subset, whereas patients with cholesterol levels 200 mg/dL and LDL 130 mg/dL were considered hypercholesterolemic.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Normo- and Hypercholesterolemic Patients

Figure 1A illustrates basal blood pressure levels in both groups, displaying no significant differences between groups. Figure 1B compares relative systolic blood pressure elevation in normo- and hypercholesterolemic patients. Angiotensin II caused a more profound blood pressure increase in hypercholesterolemic individuals. Hypercholesterolemic patients (n=8) were treated for 6 weeks with 20 to 40 mg atorvastatin or simvastatin to lower cholesterol plasma levels (LDL >200 mg/mL, 40 mg/day; LDL <200 mg/mL, 20 mg/day). Cholesterol decreased from 293±15 to 228±14 mg/dL, LDL from 223±13 to 151±16 mg/dL. HDL concentrations was comparable between groups (48±3 versus 49±4 mg/dL). Triglycerides amounted to 192.2±35.5 before and 186.6± 32.2 mg/dL after treatment. Cholesterol-lowering therapy caused a significant decrease in angiotensin II-induced blood pressure increase (Figure 1C).

View larger version (33K): [in this window] [in a new window]   Figure 1. A, Basal blood pressure in normo- and hypercholesterolemic (Normochol, Hyperchol) individuals (n= 19 and 20, respectively). Mean values of 3 measurements in 2-minute intervals were used. Syst indicates systolic; and diast, diastolic. B, Angiotensin II (0.5 to 20 ng · kg-1 · min-1) was infused. The effect of angiotensin II on systolic blood pressure in normo- and hypercholesterolemic individuals is shown. C, Measurements were applied to hypercholesterolemic individuals before (Hyperchol) and after (Statin) treatment period with 20 to 40 mg atorvastatin or simvastatin for 6 weeks (n=8).

Norepinephrine led to a similar increase of blood pressure in both groups, suggesting a specific effect of hypercholesterolemia on angiotensin II-driven blood pressure control (Table 2).

View this table: [in this window] [in a new window]   Table 2. Blood Pressure Increase (mm Hg) on Angiotensin II and Norepinephrine

AT1 receptor expression was quantified by radioligand binding assays in isolated intact platelets. Figure 2A shows a saturation binding experiments with ¹²⁵I-angiotensin II. Figure 2B illustrates data of AT1 receptor density in 19 normo- and 20 hypercholesterolemic patients. Whereas the ligand affinity was not significantly different between subsets (K_d=1.6 nmol/L [95%CI 0.3 to 2.9 nmol/L] versus 2.4 nmol/L [95%CI 0.9 to 3.9 nmol/L]), the AT1 receptor density was increased in hypercholesterolemic patients (B_max=5.2±0.7 fmol/mg protein) in comparison to normocholesterolemic men (B_max=2.1±0.2 fmol/mg protein; P<0.05).

View larger version (25K): [in this window] [in a new window]   Figure 2. A, Representative saturation binding experiments for 125I-angiotensin II on isolated platelets. B, AT1 receptor density in 19 normo- and 20 hypercholesterolemic individuals. C, AT1 receptor density in patients before (Hyperchol) and after treatment with 20 to 40 mg atorvastatin or simvastatin for 6 weeks (Statin) (n=8).

Lipid-lowering therapy led to a significant decrease in AT1 receptor density from B_max=5.6±1.4 to B_max=1.5±0.4 fmol/mg protein in individuals on statins (n=8) (Figure 2C, P<0.05). Receptor affinity was unchanged (K_d=1.8 nmol/L [95%CI -0.5 to 4.2 nmol/L[ versus 1.6 nmol [95%CI 0.4 to 2.7 nmol/L]) between groups.

Figure 3 shows the statistically significant correlation between AT1 receptor density and LDL plasma concentration. The results suggest that increasing cholesterol plasma levels induces closely dependent elevations of AT1 receptor expression, which causes a more profound angiotensin II-induced blood pressure increase.

View larger version (16K): [in this window] [in a new window]   Figure 3. Regression analysis of plasma LDL concentration and platelet AT1 receptor density.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Hypercholesterolemia is associated with significant overexpression of AT1 receptors in humans, leading to a profound increase of angiotensin II-induced blood pressure elevation.

Elevated LDL plasma levels are a major risk factor for the development of coronary heart disease, the leading cause of death in the western world.¹ LDL and especially oxidized LDL has been implicated in impaired release of nitric oxide, damage of endothelial and VSMC, adhesion of mononuclear cells on the vessel wall, blood coagulation, cytokine release, and enhanced efficacy of vascular growth factors.^{9 10 11 12} Nevertheless, it is well-known, but mechanistically unsettled, that hypertension is frequently attended by hypercholesterolemia and vice versa, both potentiating each other with respect to the development of coronary heart disease.⁴

The AT1 receptor mediates many biological effects of the renin-angiotensin system, including vasoconstriction, cell growth, water and electrolyte homeostasis, and sympathetic activation.⁶ In view of the pathogenesis of hypertension and atherosclerosis and their interactions, hypercholesterolemia-induced AT1 receptor overexpression may have major implications.¹ The angiotensin II-induced vasoconstriction is enhanced during hypercholesterolemia. In the beginning, this may not have tremendous impact on basal conditions, because negative feedback regulation of the renin-angiotensin system may occur. Nevertheless, situations of enhanced neurohumoral activation such as mental stress and exercising or additional risk factors like smoking or increased salt intake may, under these circumstances, lead to greater blood pressure elevations that may chronically accumulate to established hypertension.² The AT1 receptor induces growth of VSMC, an event thought to be of central relevance for the pathogenesis of atherosclerosis.^{6 9} AT1 receptor overexpression during hypercholesterolemia may accelerate this process.³ The AT1 receptor is a major source of reactive oxygen species (ROS) in the vessel wall.¹² These free radicals are also potentially involved in the development of cardiovascular diseases.¹³ Interestingly, ROS production is enhanced in hypercholesterolemia.¹⁴ Moreover, this ROS excess was normalized in hypercholesterolemic animals through AT1 receptor antagonism,¹⁵ suggesting that AT1 receptor overexpression is a decisive mechanism in the pathogenesis of lipid-induced atherosclerosis.⁴ In men with coronary heart disease, ACE inhibitors improve endothelial dysfunction closely related to ROS production and atherosclerosis.¹⁶ This effect was especially pronounced in hypercholesterolemic individuals.⁵ Treatment with statins causes a decrease of mortality and morbidity in normo- and hypercholesterolemic patients.^{2 3 4 5} There is increasing evidence that these drugs exert this beneficial effect only in part by lowering of plasma cholesterol concentrations. Beside other cellular effects, statins directly downregulate AT1 receptor expression in isolated VSMC.¹⁷ The present data support the notion that this effect may play an important role in vivo; AT1 receptor density was reduced in the statin treatment group to an extent that could not be predicted in view of the changes in cholesterol levels. Namely, AT1 receptor density was reduced by statins to 26% compared with levels before treatment, although LDL levels were only reduced to 70% of the pretreatment level. In contrast, in the untreated groups, LDL plasma concentrations were 218 versus 106 mg/dL (48%), but AT1 receptor density was only decreased to 40% in normocholesterolemic compared with hypercholesterolemic patients.

Thus, the hypercholesterolemia-induced overexpression of AT1 receptor expression resembles a novel concept that advances our understanding of the pathogenesis of chronic cardiovascular disease. Intervention trials are warranted; these will test the effect of AT1 receptor antagonists or ACE inhibitors on atherosclerosis and hypertension related to hypercholesterolemia with respect to progression and mortality of the underlying diseases. In addition, AT1 receptor downregulation could in part explain the cholesterol-independent beneficial effects of statins.

	Acknowledgments

 
This work was supported by the Deutsche Forschungsgemeinschaft, the Köln Fortune Program/Faculty of Medicine, University of Cologne, and by the Deutsche Herzstiftung.

	Footnotes

 
¹ Drs Nickenig and Bäumer contributed equally to this study.

Received June 21, 1999; revision received September 14, 1999; accepted September 23, 1999.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S, Kannel WB. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA. 1986;256:2835–2838.[Abstract]
   
2. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–1307.[Abstract/Free Full Text]
   
3. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349–1357.[Abstract/Free Full Text]
   
4. Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men. Lancet. 1986;2:933–936.[Medline] [Order article via Infotrieve]
   
5. Libby P, Miao P, Ordovas JM, Schaefer EJ. Lipoproteins increase growth of mitogen-stimulated arterial smooth muscle cells. J Cell Physiol. 1985;124:1–8.[Medline] [Order article via Infotrieve]
   
6. Griendling KK, Murphy TJ, Alexander RW. Molecular biology of the renin-angiotensin system. Circulation. 1993;87:1816–1828.[Free Full Text]
   
7. Nickenig G, Sachinidis A, Michaelsen F, Böhm M, Seewald S, Vetter H. Upregulation of vascular angiotensin II receptor gene expression by low-density lipoprotein in vascular smooth muscle cells. Circulation. 1997;95:473–478.[Abstract/Free Full Text]
   
8. Nickenig G, Jung O, Strehlow K, Zolk O, Linz W, Schölkens BA, Böhm M. Hypercholesterolemia is associated with enhanced angiotensin AT1-receptor expression. Am J Physiol. 1997;272:H2701–H2707.[Abstract/Free Full Text]
   
9. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801–809.[Medline] [Order article via Infotrieve]
   
10. Beisiegel U. Lipoprotein metabolism. Eur Heart J. 1998;19(suppl A):A20–A23.
    
11. Hajjar DP, Haberland ME. Lipoprotein trafficking in vascular cells. Molecular Trojan horses and cellular saboteurs. J Biol Chem. 1997;272:22975–22978.[Free Full Text]
    
12. Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994;74:1141–1148.[Abstract/Free Full Text]
    
13. Darley-Usmar VM, McAndrew J, Patel R, Moellering D, Lincoln TM, Jo H, Cornwell T, Digerness S, White CR. Nitric oxide, free radicals and cell signaling in cardiovascular disease. Biochem Soc Trans. 1997;25:925–929.[Medline] [Order article via Infotrieve]
    
14. Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993;91:2546–2551.
    
15. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Bräsen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Böhm M, Meinertz T, Münzel T. Increased NADH-oxidase mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin angiotensin system. Circulation. 1999;99:2027–2033.[Abstract/Free Full Text]
    
16. Mancini GB, Henry GC, Macaya C, O’Neill BJ, Pucillo AL, Carere RG, Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard AC, Pepine CJ, Pitt B. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing endothelial Dysfunction) Study. Circulation. 1996;94:258–265.[Abstract/Free Full Text]
    
17. Wassmann S, Nickenig G, Böhm M. HMG-CoA reductase inhibitor atorvastatin downregulates AT1 receptor gene expression and cell proliferation in vascular smooth muscle cells. Kidney Blood Press Res. 1999;21:392–393.
    

This article has been cited by other articles:

				O. Adam, H.-R. Neuberger, M. Bohm, and U. Laufs Prevention of Atrial Fibrillation With 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Circulation, September 16, 2008; 118(12): 1285 - 1293. [Full Text] [PDF]

				L. Guasti, F. Marino, M. Cosentino, R. C. Maio, E. Rasini, M. Ferrari, L. Castiglioni, C. Klersy, G. Gaudio, A. M. Grandi, et al. Prolonged statin-associated reduction in neutrophil reactive oxygen species and angiotensin II type 1 receptor expression: 1-year follow-up Eur. Heart J., May 1, 2008; 29(9): 1118 - 1126. [Abstract] [Full Text] [PDF]

				B. A. Golomb, J. E. Dimsdale, H. L. White, J. B. Ritchie, and M. H. Criqui Reduction in Blood Pressure With Statins: Results From the UCSD Statin Study, a Randomized Trial Arch Intern Med, April 14, 2008; 168(7): 721 - 727. [Abstract] [Full Text] [PDF]

				K. Ramasubbu, J. Estep, D. L. White, A. Deswal, and D. L. Mann Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J. Am. Coll. Cardiol., January 29, 2008; 51(4): 415 - 426. [Abstract] [Full Text] [PDF]

				M. Oktem, I. Esinler, D. Eroglu, N. Haberal, N. Bayraktar, and H. B. Zeyneloglu High-dose atorvastatin causes regression of endometriotic implants: a rat model Hum. Reprod., May 1, 2007; 22(5): 1474 - 1480. [Abstract] [Full Text] [PDF]

				P. Strazzullo, S. M. Kerry, A. Barbato, M. Versiero, L. D'Elia, and F. P. Cappuccio Do Statins Reduce Blood Pressure?: A Meta-Analysis of Randomized, Controlled Trials Hypertension, April 1, 2007; 49(4): 792 - 798. [Abstract] [Full Text] [PDF]

				I. H. Zucker Novel Mechanisms of Sympathetic Regulation in Chronic Heart Failure Hypertension, December 1, 2006; 48(6): 1005 - 1011. [Full Text] [PDF]

				P. van der Harst, A. A. Voors, W. H. van Gilst, M. Bohm, and D. J. van Veldhuisen Statins in the treatment of chronic heart failure: Biological and clinical considerations Cardiovasc Res, August 1, 2006; 71(3): 443 - 454. [Abstract] [Full Text] [PDF]

				N. A.J. van der Linde, E. J.G. Sijbrands, F. Boomsma, and A. H. van den Meiracker Effect of Low-Density Lipoprotein Cholesterol on Angiotensin II Sensitivity: A Randomized Trial With Fluvastatin Hypertension, June 1, 2006; 47(6): 1125 - 1130. [Abstract] [Full Text] [PDF]

				U. Forstermann and T. Munzel Endothelial Nitric Oxide Synthase in Vascular Disease: From Marvel to Menace Circulation, April 4, 2006; 113(13): 1708 - 1714. [Abstract] [Full Text] [PDF]

				A Mezzetti Pharmacological modulation of plaque instability Lupus, September 1, 2005; 14(9): 769 - 772. [Abstract] [PDF]

				T. Munzel, A. Daiber, V. Ullrich, and A. Mulsch Vascular Consequences of Endothelial Nitric Oxide Synthase Uncoupling for the Activity and Expression of the Soluble Guanylyl Cyclase and the cGMP-Dependent Protein Kinase Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1551 - 1557. [Abstract] [Full Text] [PDF]

				K. K. Koh, M. J. Quon, S. H. Han, J. Y. Ahn, D. K. Jin, H. S. Kim, D. S. Kim, and E. K. Shin Vascular and Metabolic Effects of Combined Therapy With Ramipril and Simvastatin in Patients With Type 2 Diabetes Hypertension, June 1, 2005; 45(6): 1088 - 1093. [Abstract] [Full Text] [PDF]

				C. Zhang, J. D. Knudson, S. Setty, A. Araiza, U. D. Dincer, L. Kuo, and J. D. Tune Coronary arteriolar vasoconstriction to angiotensin II is augmented in prediabetic metabolic syndrome via activation of AT1 receptors Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2154 - H2162. [Abstract] [Full Text] [PDF]

				V. Adams, A. Linke, N. Krankel, S. Erbs, S. Gielen, S. Mobius-Winkler, J. F. Gummert, F. W. Mohr, G. Schuler, and R. Hambrecht Impact of Regular Physical Activity on the NAD(P)H Oxidase and Angiotensin Receptor System in Patients With Coronary Artery Disease Circulation, February 8, 2005; 111(5): 555 - 562. [Abstract] [Full Text] [PDF]

				R. A. Malik, I. J. Schofield, A. Izzard, C. Austin, G. Bermann, and A. M. Heagerty Effects of Angiotensin Type-1 Receptor Antagonism on Small Artery Function in Patients With Type 2 Diabetes Mellitus Hypertension, February 1, 2005; 45(2): 264 - 269. [Abstract] [Full Text] [PDF]

				T. Petnehazy, K. Y. Stokes, J. M. Russell, and D. N. Granger Angiotensin II Type-1 Receptor Antagonism Attenuates the Inflammatory and Thrombogenic Responses to Hypercholesterolemia in Venules Hypertension, February 1, 2005; 45(2): 209 - 215. [Abstract] [Full Text] [PDF]

				A. Daugherty, D. L. Rateri, H. Lu, T. Inagami, and L. A. Cassis Hypercholesterolemia Stimulates Angiotensin Peptide Synthesis and Contributes to Atherosclerosis Through the AT1A Receptor Circulation, December 21, 2004; 110(25): 3849 - 3857. [Abstract] [Full Text] [PDF]

				K. K. Koh, M. J. Quon, S. H. Han, W.-J. Chung, J. Y. Ahn, Y.-H. Seo, M. H. Kang, T. H. Ahn, I. S. Choi, and E. K. Shin Additive Beneficial Effects of Losartan Combined With Simvastatin in the Treatment of Hypercholesterolemic, Hypertensive Patients Circulation, December 14, 2004; 110(24): 3687 - 3692. [Abstract] [Full Text] [PDF]

				S. Wassmann, T. Czech, M. van Eickels, I. Fleming, M. Bohm, and G. Nickenig Inhibition of Diet-Induced Atherosclerosis and Endothelial Dysfunction in Apolipoprotein E/Angiotensin II Type 1A Receptor Double-Knockout Mice Circulation, November 9, 2004; 110(19): 3062 - 3067. [Abstract] [Full Text] [PDF]

				G. Nickenig Should Angiotensin II Receptor Blockers and Statins Be Combined? Circulation, August 24, 2004; 110(8): 1013 - 1020. [Full Text] [PDF]

				K. K. Koh, J. W. Son, J. Y. Ahn, D. S. Kim, D. K. Jin, H. S. Kim, S. H. Han, Y.-H. Seo, W.-J. Chung, W. C. Kang, et al. Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients Hypertension, August 1, 2004; 44(2): 180 - 185. [Abstract] [Full Text] [PDF]

				M.-S. Zhou, E. A. Jaimes, and L. Raij Atorvastatin Prevents End-Organ Injury in Salt-Sensitive Hypertension: Role of eNOS and Oxidant Stress Hypertension, August 1, 2004; 44(2): 186 - 190. [Abstract] [Full Text] [PDF]

				F. Cipollone, M. Fazia, A. Iezzi, B. Pini, C. Cuccurullo, M. Zucchelli, D. de Cesare, S. Ucchino, F. Spigonardo, M. De Luca, et al. Blockade of the Angiotensin II Type 1 Receptor Stabilizes Atherosclerotic Plaques in Humans by Inhibiting Prostaglandin E2-Dependent Matrix Metalloproteinase Activity Circulation, March 30, 2004; 109(12): 1482 - 1488. [Abstract] [Full Text] [PDF]

				J. I. Osende, M. Ruiz-Ortega, L. M. Blanco-Colio, and J. Egido Statins to prevent cardiovascular events in hypertensive patients. The ASCOT-LLA study Nephrol. Dial. Transplant., March 1, 2004; 19(3): 528 - 531. [Full Text] [PDF]

				B. D. Wyse, I. A. Prior, H. Qian, I. C. Morrow, S. Nixon, C. Muncke, T. V. Kurzchalia, W. G. Thomas, R. G. Parton, and J. F. Hancock Caveolin Interacts with the Angiotensin II Type 1 Receptor during Exocytic Transport but Not at the Plasma Membrane J. Biol. Chem., June 20, 2003; 278(26): 23738 - 23746. [Abstract] [Full Text] [PDF]

				B. M. Singh and J. L. Mehta Interactions Between the Renin-Angiotensin System and Dyslipidemia: Relevance in the Therapy of Hypertension and Coronary Heart Disease Arch Intern Med, June 9, 2003; 163(11): 1296 - 1304. [Abstract] [Full Text] [PDF]

				R. U. Pliquett, K. G. Cornish, J. D. Peuler, and I. H. Zucker Simvastatin Normalizes Autonomic Neural Control in Experimental Heart Failure Circulation, May 20, 2003; 107(19): 2493 - 2498. [Abstract] [Full Text] [PDF]

				M. Rodriguez-Porcel, A. Lerman, J. Herrmann, R. S. Schwartz, T. Sawamura, M. Condorelli, C. Napoli, and L. O. Lerman Hypertension exacerbates the effect of hypercholesterolemia on the myocardial microvasculature Cardiovasc Res, April 1, 2003; 58(1): 213 - 221. [Abstract] [Full Text] [PDF]

				M. Horiuchi, T.-X. Cui, Z. Li, J.-M. Li, H. Nakagami, and M. Iwai Fluvastatin Enhances the Inhibitory Effects of a Selective Angiotensin II Type 1 Receptor Blocker, Valsartan, on Vascular Neointimal Formation Circulation, January 7, 2003; 107(1): 106 - 112. [Abstract] [Full Text] [PDF]

				C. Zoja, D. Corna, D. Camozzi, D. Cattaneo, D. Rottoli, C. Batani, C. Zanchi, M. Abbate, and G. Remuzzi How To Fully Protect the Kidney in a Severe Model of Progressive Nephropathy: A Multidrug Approach J. Am. Soc. Nephrol., December 1, 2002; 13(12): 2898 - 2908. [Abstract] [Full Text] [PDF]

				D Patterson, J B C Dick, and A D Struthers Intensive statin treatment improves baroreflex sensitivity: another cardioprotective mechanism for statins? Heart, October 1, 2002; 88(4): 415 - 416. [Full Text] [PDF]

				L. T. McGrath, L. Dixon, D. R. Morgan, and G. E. McVeigh Production of 8-epi prostaglandin F2{alpha} in human platelets during administration of organic nitrates J. Am. Coll. Cardiol., August 21, 2002; 40(4): 820 - 825. [Abstract] [Full Text] [PDF]

				S. Delbosc, J.-P. Cristol, B. Descomps, A. Mimran, and B. Jover Simvastatin Prevents Angiotensin II-Induced Cardiac Alteration and Oxidative Stress Hypertension, August 1, 2002; 40(2): 142 - 147. [Abstract] [Full Text] [PDF]

				S. Wassmann, S. Hilgers, U. Laufs, M. Bohm, and G. Nickenig Angiotensin II Type 1 Receptor Antagonism Improves Hypercholesterolemia-Associated Endothelial Dysfunction Arterioscler. Thromb. Vasc. Biol., July 1, 2002; 22(7): 1208 - 1212. [Abstract] [Full Text] [PDF]

				G. Sopko Preventing Cardiac Events and Restenosis After Percutaneous Coronary Intervention JAMA, June 26, 2002; 287(24): 3259 - 3261. [Full Text] [PDF]