This Article 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 Vaughan, D. E. Search for Related Content PubMed PubMed Citation Articles by Vaughan, D. E. Related Collections ACE/Angiotension receptors Animal models of human disease Pathophysiology Mechanism of atherosclerosis/growth factors

(Circulation. 2000;101:1496.)
© 2000 American Heart Association, Inc.

Editorial

AT₁ Receptor Blockade and Atherosclerosis

Hopeful Insights Into Vascular Protection

Douglas E. Vaughan, MD

From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to Douglas E. Vaughan, MD, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.

Key Words: Editorials • atherosclerosis • angiotensin • receptors

Angiotensin II (Ang II) is a potent vasoconstrictor, and apart from its effects on blood pressure, this short-lived peptide been strongly implicated in the pathogenesis of ischemic cardiovascular disease. At the molecular and cellular levels, Ang II promotes a complex array of effects that may promote the initiation and progression of atherosclerosis.

At each of the well-defined stages of atherosclerosis, Ang II has the potential to contribute to the vascular pathobiology. For example, type 1 atherosclerotic lesions are defined by the presence of increased numbers of macrophages in the vascular intima and by the formation of foam cells.¹ At this early stage of atherosclerosis, Ang II facilitates the recruitment of monocytes/macrophages into the vessel wall by stimulating the production of monocyte chemoattractant protein² and vascular cell adhesion molecule-1³ by smooth muscle cells. Once monocytes are localized to the blood vessel wall, these cells undergo a phenotypic transformation and take up oxidized LDL, leading to foam cell formation. Ang II indirectly facilitates this step by activating membrane-based NADP/NADPH oxidase,⁴ which promotes the production of superoxide radicals (O₂^-). The oxidant stress triggered by Ang II may contribute to enhanced oxidation of LDL and degradation of nitric oxide (NO). The loss of NO has many vascular biological ramifications, because NO is widely considered a vascular protective molecule that retards the development of atherosclerosis.⁵ Within the last 2 years, a new receptor, biochemically distinct from the scavenger receptor, has been identified that mediates the binding and uptake of oxidized LDL (oxLDL) by vascular tissue.⁶ The expression of this oxLDL receptor has recently been shown to be regulated by Ang II,⁷ and this may contribute to endothelial dysfunction and to accumulation of lipid in atherosclerotic plaques. Later stages of atherosclerosis are characterized by increased smooth muscle cell content, increased matrix deposition, and the accumulation of fibrinogen and fibrin in the plaque.⁸ The pluripotent peptide Ang II likely contributes to all of these processes as well. Ang II is a well-characterized mitogen for vascular smooth muscle cells and stimulates the accumulation of extracellular matrix directly and indirectly by stimulating the production of transforming growth factor-ß.⁹ Studies from this laboratory and others have shown that Ang II can promote the production of plasminogen activator inhibitor-1 in vascular tissue.^{10 11} This leads to reduced efficiency of the fibrinolytic system and likely contributes to the deposition of fibrin and fibrinogen typically seen in the late stages of atherosclerosis.

Many of the proatherosclerotic effects of Ang II are mediated by the binding of the peptide to the type 1 angiotensin (AT₁) receptor. In this issue of Circulation, Strawn and colleagues¹² describe the effects of the AT₁ receptor antagonist losartan on the development of atherosclerosis in cholesterol-fed cynomolgus monkeys. Animals were fed an atherogenic diet for a total of 20 weeks. Starting in week 12 of the study, animals were randomly assigned treatment to losartan or vehicle control delivered by osmotic minipumps implanted subcutaneously. At the end of the study period (20 weeks), the animals were killed, and the extent of atherosclerosis was determined by classic methods. Losartan had a consistent effect on reducing the extent of fatty streak formation by 50% in the aorta. The coronary arteries of losartan-treated animals also exhibited reduced arterial thickness. This reduction in the development of vascular pathology was not attributable to a decrease in plasma cholesterol. Furthermore, although losartan is primarily used for the treatment of hypertension in humans, these rather dramatic effects on the extent of fatty streak formation were not accompanied by a reduction in blood pressure in losartan-treated animals.

The present study confirms and extends prior observations made in a variety of experimental models indicating that interruption of the renin-angiotensin system can forestall the development of atherosclerosis. This was first shown with the ACE inhibitor captopril in Watanabe heritable hyperlipidemic rabbits.¹³ Subsequently, similar results have been reported in other animal models of atherosclerosis, including genetically modified mice,¹⁴ as well as rabbits¹⁵ and monkeys¹⁶ fed an atherogenic diet. The present study suggests that AT₁ receptor blockade blunts the development of atherosclerosis in the absence of a blood pressure–lowering effect. This finding contradicts prior studies in rabbits¹⁷ indicating that the antiatherosclerotic effects of ACE inhibition or AT₁ receptor blockade were dependent on blood pressure reduction. The reasons for this discrepancy are unclear but may reflect differences in animal models, pharmacological properties of the agents used, or other unidentified factors. It suggests that in primates, Ang II plays a role in atherosclerosis in the absence of hypertension.

If the same relationship holds true in humans, then we might expect to see clinical benefits from ACE inhibitors and AT₁ receptor blockers in the prevention of ischemic cardiovascular events. Certainly, the Survival And Ventricular Enlargement (SAVE)¹⁸ and Studies Of Left Ventricular Dysfunction (SOLVD)¹⁹ trials suggested that the long-term administration of ACE inhibitors to patients with left ventricular dysfunction reduced the incidence of recurrent myocardial infarction. Whether or not interruption of the renin-angiotensin system reduces the incidence of myocardial infarction or cardiovascular death in normotensive subjects with preserved ventricular function is the subject of intense speculation at present. The recently reported results of the Heart Outcomes Prevention Evaluation (HOPE) trial demonstrate that ACE inhibition reduces the rates of death, myocardial infarction, and stroke in a high-risk population.²⁰ The study by Strawn and colleagues¹² suggests that clinical trials designed to test the hypothesis that AT₁ receptor blockade retards the development of atherosclerosis in humans deserve to be performed.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

1. Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W Jr, Rosenfield ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb. 1994;14:840–856.[Abstract/Free Full Text]
   
2. Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM. Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. Circ Res. 1998;83:952–959.[Abstract/Free Full Text]
   
3. Tummala PE, Chen XL, Sundell CL, Laursen JB, Hammes CP, Alexander RW, Harrison DG, Medford RM. Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: a potential link between the renin-angiotensin system and atherosclerosis. Circulation. 1999;100:1223–1229.[Abstract/Free Full Text]
   
4. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Invest. 1996;97:1916–1923.[Medline] [Order article via Infotrieve]
   
5. Maxwell AJ, Cooke JP. The role of nitric oxide in atherosclerosis. Coron Artery Dis. 1999;10:277–286.[Medline] [Order article via Infotrieve]
   
6. Sawamura T, Kume N, Aoyama T, Moriwaki H, Hoshikawa H, Aiba Y, Tanaka T, Miwa S, Katsura Y, Kita T, Masaki T. An endothelial receptor for oxidized low-density lipoprotein. Nature. 1997;386:73–77.[Medline] [Order article via Infotrieve]
   
7. Li DY, Zhang YC, Philips MI, Sawamura T, Mehta JL. Upregulation of endothelial receptor for oxidized low-density lipoprotein (LOX-1) in cultured human coronary artery endothelial cells by angiotensin II type 1 receptor activation [see comments]. Circ Res. 1999;84:1043–1049.[Abstract/Free Full Text]
   
8. Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol. 1995;15:1512–1531.[Abstract/Free Full Text]
   
9. Omura T, Kim S, Takeuchi K, Iwao H, Takeda T. Transforming growth factor beta 1 and extracellular matrix gene expression in isoprenaline induced cardiac hypertrophy: effects of inhibition of the renin-angiotensin system. Cardiovasc Res. 1994;28:1835–1842.[Abstract/Free Full Text]
   
10. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells: a potential link between the renin-angiotensin system and thrombosis. J Clin Invest. 1995;95:995–1001.[Medline] [Order article via Infotrieve]
    
11. Hamdan AD, Quist WC, Gagne JB, Feener EP. Angiotensin-converting enzyme inhibition suppresses plasminogen activator inhibitor-1 expression in the neointima of balloon-injured rat aorta. Circulation. 1996;93:1073–1078.[Abstract/Free Full Text]
    
12. Strawn WB, Chappell MC, Dean RH, Kivlighn S, Ferrario CM. Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia. Circulation. 2000;101:1586–1593.[Abstract/Free Full Text]
    
13. Chobanian AV, Haudenschild CC, Nickerson C, Drago R. Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension. 1990;15:327–331.[Abstract/Free Full Text]
    
14. Hayek T, Attias J, Smith J, Breslow JL, Keidar S. Antiatherosclerotic and antioxidative effects of captopril in apolipoprotein E-deficient mice. J Cardiovasc Pharmacol. 1998;31:540–544.[Medline] [Order article via Infotrieve]
    
15. Schuh JR, Blehm DJ, Frierdich GE, McMahon EG, Blaine EH. Differential effects of renin-angiotensin system blockade on atherogenesis in cholesterol-fed rabbits. J Clin Invest. 1993;91:1453–1458.[Medline] [Order article via Infotrieve]
    
16. Aberg G, Ferrer P. Effects of captopril on atherosclerosis in cynomolgus monkeys. J Cardiovasc Pharmacol. 1990;15:S65–S72.
    
17. Hope S, Brecher P, Chobanian AV. Comparison of the effects of AT1 receptor blockade and angiotensin converting enzyme inhibition on atherosclerosis. Am J Hypertens. 1999;12:28–34.[Medline] [Order article via Infotrieve]
    
18. Rutherford JD, Pfeffer MA, Moye LA, Davis BR, Flaker GC, Kowey PR, Lamas GA, Miller HS, Packer M, Rouleau JL, Braunwald E. Effects of captopril on ischemic events after myocardial infarction: results of the Survival and Ventricular Enlargement trial: SAVE Investigators. Circulation. 1994;90:1731–1738.[Abstract/Free Full Text]
    
19. Yusuf S, Pepine CJ, Garces C, Pouleur H, Salem D, Kostis J, Benedict C, Rousseau M, Bourassa M, Pitt B. Effect of enalapril on myocardial infarction and unstable angina in patients with low ejection fractions. Lancet. 1992;340:1173–1178.[Medline] [Order article via Infotrieve]
    
20. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitior, ramipril, on cardiovascular events in high-risk patients. N Engl J Med.. 2000;342:145–153.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				I. Imayama, T. Ichiki, D. Patton, K. Inanaga, R. Miyazaki, H. Ohtsubo, Q. Tian, K. Yano, and K. Sunagawa Liver X Receptor Activator Downregulates Angiotensin II Type 1 Receptor Expression Through Dephosphorylation of Sp1 Hypertension, June 1, 2008; 51(6): 1631 - 1636. [Abstract] [Full Text] [PDF]

				M. M. Martin, J. A. Buckenberger, J. Jiang, G. E. Malana, G. J. Nuovo, M. Chotani, D. S. Feldman, T. D. Schmittgen, and T. S. Elton The Human Angiotensin II Type 1 Receptor +1166 A/C Polymorphism Attenuates MicroRNA-155 Binding J. Biol. Chem., August 17, 2007; 282(33): 24262 - 24269. [Abstract] [Full Text] [PDF]

				M. T. Johnstone, A. S. Perez, I. Nasser, R. Stewart, A. Vaidya, F. Al Ammary, B. Schmidt, G. Horowitz, J. Dolgoff, J. Hamilton, et al. Angiotensin Receptor Blockade With Candesartan Attenuates Atherosclerosis, Plaque Disruption, and Macrophage Accumulation Within the Plaque in a Rabbit Model Circulation, October 5, 2004; 110(14): 2060 - 2065. [Abstract] [Full Text] [PDF]

				S. C. Fagan, D. C. Hess, E. J. Hohnadel, D. M. Pollock, and A. Ergul Targets for Vascular Protection After Acute Ischemic Stroke Stroke, September 1, 2004; 35(9): 2220 - 2225. [Abstract] [Full Text] [PDF]

				N. Werner and G. Nickenig AT1 receptors in atherosclerosis: biological effects including growth, angiogenesis, and apoptosis Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A9 - A13. [Abstract] [PDF]

				G. Nickenig and D. G. Harrison The AT1-Type Angiotensin Receptor in Oxidative Stress and Atherogenesis: Part I: Oxidative Stress and Atherogenesis Circulation, January 22, 2002; 105(3): 393 - 396. [Full Text] [PDF]

				G. Nickenig, F. Michaelsen, C. Muller, A. Berger, T. Vogel, A. Sachinidis, H. Vetter, and M. Bohm Destabilization of AT1 Receptor mRNA by Calreticulin Circ. Res., January 11, 2002; 90(1): 53 - 58. [Abstract] [Full Text] [PDF]

This Article 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 Vaughan, D. E. Search for Related Content PubMed PubMed Citation Articles by Vaughan, D. E. Related Collections ACE/Angiotension receptors Animal models of human disease Pathophysiology Mechanism of atherosclerosis/growth factors