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(Circulation Research. 2007;101:116.)
© 2007 American Heart Association, Inc.

Editorials

Old Drug, New Tricks

The Unexpected Effect of Doxazosin on High-Density Lipoprotein

Alan T. Remaley

From the National Institutes of Health, National Heart, Lung, and Blood Institute, Vascular Medicine Branch, Lipoprotein Metabolism Section.

Correspondence to Alan T. Remaley, National Institutes of Health, 10 Center Dr., Bldg. 10/Rm. 2C-433, Bethesda, MD 20892. E-mail aremaley{at}nih.gov

See related article, pages 156–165

Key Words: cholesterol • atherosclerosis • HDL • doxazosin • ABCA1

Ironically, even though there are currently only a few drugs to specifically treat low high-density lipoprotein (HDL), numerous drugs have been observed to inadvertently alter HDL levels.¹ This has been particularly noted for some antihypertensive drugs. Because they are used long-term, any positive or negative effect of antihypertensive drugs on lipids and lipoproteins can significantly impact on their effectiveness in preventing cardiovascular disease. Recently, advances in our understanding of HDL metabolism have helped us to unravel the mechanism of action of these and other drugs that unexpectedly alter HDL levels. This work has largely been led by the laboratory of Shinji Yokoyama and colleagues, who have previously identified the mechanism of action of three drugs on HDL metabolism. Probucol, which has been used to treat patients at risk for cardiovascular disease, is an antioxidant and lowers LDL, but it also lowers HDL. Probucol is now known to decrease HDL by inhibiting the activity of the ABCA1 transporter,² a key protein involved in reverse cholesterol transport pathway and in HDL biogenesis.³ Verapamil, a calcium channel blocker, which can be used as antihypertensive and antiarrhythmic agent, and fenofibrate, a lipid-lowering drug, both raise HDL by increasing the gene expression of the ABCA1 transporter.^4,5 In this issue of Circulation Research,⁶ Iwamoto et al describe the mechanism of action of a fourth agent that unexpectedly alters HDL, namely the antihypertensive agent doxazosin. The results of this study raise the possibility of a new strategy for developing drugs to increase HDL.

Doxazosin (Cardura) is a quinazoline based compound that is sold by Pfizer and is a long lasting selective inhibitor of the -1a subtype of adrenergic receptors. It blocks the binding of norepinephrine to adrenergic receptors in the autonomic nervous system, which leads to decreased vascular tone from the relaxation of smooth muscle cells. It thus reduces peripheral vascular resistance and is an effective agent for lowering blood pressure.⁷ It can be used as single agent but is also often used in conjunction with other anti-hypertensive medications for those patients that need more than one antihypertensive drug. Doxazosin can also be used to treat urinary retention problems in patients with benign prostatic hyperplasia.⁸ By acting as an -1a adrenergic antagonist, it reduces the tone of smooth muscles within the prostate and in the neck of the bladder, thus relieving the urinary outflow obstruction symptoms from an enlarged prostate. Interestingly, it appears to also have some other long-term beneficial effects on urinary retention symptoms, by possibly increasing apoptosis and reducing prostrate growth.⁹ Independent from its effect as an -1a adrenergic antagonist, chronic treatment with doxazosin is known to alter the expression of many genes, some of which are related to apoptosis.¹⁰

Doxazosin was first noted to alter lipid and lipoprotein levels in the 1980’s in studies examining its utility as an antihypertensive agent. Its effect on lipids is dose-dependent and variable, but many studies have shown that it has a beneficial effect on lipids by modestly lowering both total cholesterol and triglycerides.^11–14 It has also been reported to lower LDL-C, prevent the oxidation of LDL, decrease small dense LDL, improve glucose tolerance, and decrease CRP.^15–18 In addition, HDL has been reported to be elevated by approximately 5% by treatment with doxazosin, but this has not been observed in all studies.^11–14 These changes in the lipoprotein profile, glucose tolerance, and inflammation suggest that doxazosin in some way may be altering biochemical pathways related to the metabolic syndrome. Treatment with doxazosin was estimated in one study to decrease the average 5-year risk for coronary heart disease by 15%, largely because of its beneficial effect of on lipoproteins.¹⁹ In various animal models, doxazosin has also been shown to reduce cholesterol accumulation in the vessel wall and the formation of atherosclerotic plaques.²⁰

A diagram, based on the article in this issue, on how doxazosin increases HDL is shown in the Figure. Doxazosin was first found to increase cholesterol and phospholipid efflux by approximately 50% from the macrophage cell line THP-1 to apoA-I, the main protein constituent of HDL. This effect was found to be specific for doxasosin and did not occur with other -1a adrenergic antagonists. Furthermore, ABCA1 protein was found to be increased in THP1 cells treated with doxazosin. ABCA1 is a member of the ATP Binding Cassette transporter family, and when defective leads to low HDL and Tangier disease.³ ABCA1 is expressed in the liver and intestine, where it forms HDL by transferring cholesterol and phospholipid to apoA-I. ABCA1 is also expressed in peripheral cells, such as macrophages, and mediates the removal of excess cellular cholesterol to apoA-I and its eventual return to the liver to complete the reverse cholesterol transport pathway. Thus the ability of doxazosin to increase the level of ABCA1 protein likely explains its in vivo effect on HDL and suggests that it increases HDL by increasing HDL biosynthesis and not by delaying catabolism.

View larger version (20K): [in this window] [in a new window]   Model for the effect of doxazosin on HDL biosynthesis. Doxazosin decreases the phosphorylation of the transcription factor AP2. This blocks the ability of AP2 from binding to the ABCA1 promoter and from repressing the transcription of ABCA1. In the absence of the phosphorylated form of AP2, ABCA1 transcription is turned on by the LXR/RXR transcription factor complex. After it binds its endogenous ligand, oxysterols, which increase on cholesterol-loading of cells, the LXR/RXR transcription factor complex activates the ABCA1 promoter, leading to increased expression of the ABCA1 transporter protein. ABCA1 transfers phospholipids (PL) and cholesterol (Chol) to lipid-poor apoA-I to generate nascent HDL, thus preventing the catabolism of apoA-I and raising the level of HDL.

ABCA1 is a relatively labile protein and is regulated by various transcriptional and post-transcriptional mechanisms. Doxazosin but not other -1a adrenergic antagonists was found to increase ABCA1 mRNA. Analysis of the promoter region of ABCA1 revealed the presence of a negative control element from region –368 to –147 bp, which was responsive to doxazosin treatment. This region of the promoter was found to contain an element for binding Adaptor Protein (AP) 2, a member of the retinoic acid inducible AP2 transcription factor family.²¹ By a series of chromatin immunoprecipitation studies, gel shift assays, and transfection studies, it was convincingly demonstrated that AP2 binds to the ABCA1 promoter and subsequently represses the transcription of the ABCA1 gene (Figure). Doxazosin did not alter the overall level of the AP2, but it decreased the relative amount of the phosphorylated form of AP2. Phosphorylation of AP2 is necessary for it to bind to its control element in promoters. How doxazosin decreases the phosphorylation of AP2 was not fully established, but it is known to decrease the phosphorylation and subsequent activation of several protein kinases, such as Akt/protein kinase B, which may then phosphorylate AP2.²¹

ABCA1 is an attractive drug target for raising HDL in the prevention of coronary heart disease for several reasons. First, as already discussed, ABCA1 is a key protein for the biosynthesis of HDL. Once formed, HDL can then promote the efflux of excess cellular cholesterol from peripheral cells and can also mediate its other potential beneficial properties, such as its anti-inflammatory and antioxidant effects. From transgenic mouse studies of apoA-I and ABCA1, there is strong evidence that increasing biosynthesis of HDL is antiatherogenic, whereas it is still not clear if increasing HDL by delaying its catabolism, as with CETP inhibitors, is a good approach,²² and in some cases, such as the inhibition of hepatic SR-BI, may even be even counterproductive for preventing the development of atherosclerosis.²³ Finally, the induction of ABCA1 in macrophages is especially beneficial for preventing atherosclerosis, because macrophages are heavily dependent on ABCA1 for the efflux of excess cholesterol. All these reasons account for the great interest that was generated when it was found that LXR family of transcription factors can up regulate the expression of the ABCA1 gene.²⁴ LXR, however, modulates the expression of many genes, some of which may also increase the reverse cholesterol transport pathway, but some gene changes induced by LXR are problematic. Chronic treatment of mice with LXR agonists, for example, leads to hypertriglyceridemia and a fatty liver.²⁵ Based on the results of the current study, AP2 may be an alternative approach for increasing ABCA1 expression that may obviate some of the off-target problems encountered with LXR agonists. In contrast to the positive regulation of ABCA1 by LXR, AP2 binds to a negative control element on the ABCA1 promoter, which suppresses gene expression. Thus inhibiting the kinase that phosphorylates AP2 with doxazosin or a related compound or increasing the activity of the phosphatase for AP2 may be an effective means for increasing HDL. AP2 like LXR, however, affects the expression of many genes,¹⁰ but it is encouraging that doxazosin is already an FDA approved drug. It is relatively well tolerated and has little side effects, although in the ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), a higher incidence of cardiovascular events, particularly congestive heart failure, was found for treatment with doxazosin compared with the diuretic chlorthalidone.²⁶ If AP2 does not prove to be a good target for drug development, the recent discovery of an alternative hepatic ABCA1 promoter, which helps explain the ability of statins to increase HDL, offers the possibility of the existence of other transcription factor targets for selectively modulating ABCA1 gene expression.²⁷ Investigation of other drugs that unexpectedly alter HDL levels¹ may also yield new ideas for developing drugs to raise HDL for the prevention of coronary heart disease.

	Acknowledgments

 
Sources of Funding

The author’s research is supported from intramural funds from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md.

Disclosures

None.

	Footnotes

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

	References

Top References

 

1. Young DS. Effects of Drugs on Clinical Laboratory Tests. 5th edition. Washington DC: AACC Press; 2000: 391–416.
2. Wu CA, Tsujita M, Hayashi M, Yokoyama S. Probucol inactivates ABCA1 in the plasma membrane with respect to its mediation of apolipoprotein binding and high density lipoprotein assembly and to its proteolytic degradation. J Biol Chem. 2004; 279: 30168–30174.[Abstract/Free Full Text]
3. Nofer JR, Remaley AT. Tangier disease: still more questions than answers. Cell Mol Life Sci. 2005; 62: 2150–2160.[CrossRef][Medline] [Order article via Infotrieve]
4. Suzuki S, Nishimaki-Mogami T, Tamehiro N, Inoue K, Arakawa R, Abe-Dohmae S, Tanaka AR, Ueda K, Yokoyama S. Verapamil increases the apolipoprotein-mediated release of cellular cholesterol by induction of ABCA1 expression via Liver X receptor-independent mechanism. Arterioscler Thromb Vasc Biol. 2004; 24: 519–525.[Abstract/Free Full Text]
5. Arakawa R, Tamehiro N, Nishimaki-Mogami T, Ueda K, Yokoyama S. Fenofibric acid, an active form of fenofibrate, increases apolipoprotein A-I-mediated high-density lipoprotein biogenesis by enhancing transcription of ATP-binding cassette transporter A1 gene in a liver X receptor-dependent manner. Arterioscler Thromb Vasc Biol. 2005; 25: 1193–1197.[Abstract/Free Full Text]
6. Iwamoto N, Abe-Dohmae S, Ayaori M, Tanaka N, Kusuhara M, Ohsuzu F, Yokoyama S. ATP binding cassette transporter A1 gene transcription is downregulated by the Activator Protein (AP) 2 : Doxazosin inhibits AP2 and increases high-density lipoprotein biogenesis being independent of 1-adrenoreceptor blockade. Circ Res. 2007; 101: 156–165.[Abstract/Free Full Text]
7. Ohta Y, Tsuchihashi T, Onaka U, Eto K, Ueno M. Usefulness of the alpha1-blocker doxazosin as a third-line antihypertensive drug. Hypertens Res. 2007; 30: 301–306.[CrossRef][Medline] [Order article via Infotrieve]
8. Bhardwa J, Goldstraw M, Tzortzis S, Kirby R. Finasteride and doxazosin alone or in combination for the treatment of benign prostatic hyperplasia. Expert Opin Pharmacother. 2007; 8: 1337–1344.[CrossRef][Medline] [Order article via Infotrieve]
9. Alberti C. Apoptosis induction by quinazoline-derived alpha1-blockers in prostate cancer cells: biomolecular implications and clinical relevance. Eur Rev Med Pharmacol Sci. 2007; 11: 59–64.[Medline] [Order article via Infotrieve]
10. Yono M, Foster HE, Shin D, Mane S, Latifpour J. Molecular classification of doxazosin-induced alterations in the rat prostate using gene expression profiling. Life Sci. 2005; 77: 470–479.[CrossRef][Medline] [Order article via Infotrieve]
11. Ames RP, Kiyasu JY. -1 adrenoceptor blockade with doxazosin in hypertension: effects on blood pressure and lipoproteins. J Clin Pharmacol. 1989; 29: 123–127.[Abstract]
12. Rabkin SW, Huff MW, Newman C, Sim D, Carruthers SG. Lipids and lipoproteins during antihypertensive drug therapy. Comparison of doxazosin and atenolol in a randomized, double-blind trial: the Alpha Beta Canada Study. Hypertension. 1994; 24: 241–248.[Abstract/Free Full Text]
13. Levy D, Walmsley P, Levenstein M. Principal results of the Hypertension and Lipid Trial (HALT): a multicenter study of doxazosin in patients with hypertension. Am Heart J. 1996; 131: 966–973.[CrossRef][Medline] [Order article via Infotrieve]
14. Grimm RH, Flack JM, Grandits GA, Elmer PJ, Neaton JD, Cutler JA, Lews C, McDonald R, Schoenberger J, Stamler J. Long-term effects of plasma lipids of diet and drugs to treat hypertension. Treatment of Mild Hypertension Study (TOMHS) Research Group. J Am Med Assoc. 1996; 275: 1549–1556.[Abstract]
15. Hirano T, Yoshino G, Kashiwazaki K, Adachi M. Doxazosin reduces prevalence of small dense low density lipoprotein and remnant-like particle cholesterol levels in nondiabetic and diabetic hypertensive patients. Am J Hypertens. 2001; 14: 908–913.[CrossRef][Medline] [Order article via Infotrieve]
16. Derosa G, Cicero AF, D’Angelo A, Tinelli C, Ciccarelli L, Piccinni MN, Pricolo F, Salvadeo S, Montagna L, Gravina A, Ferrari I, Galli S, Paniga S, Fogari R. Effect of doxazosin on C-reactive protein plasma levels and on nitric oxide in patients with hypertension. J Cardiovasc Pharmacol. 2006; 47: 508–512.[CrossRef][Medline] [Order article via Infotrieve]
17. Kinoshita M, Shimazu N, Fujita M, Fujimaki Y, Kojima K, Mikuni Y, Horie E, Teramoto T. Doxazosin, an 1-adrenergic antihypertensive agent, decreases serum oxidized LDL. Am J Hypertens. 2001; 14: 267–270.[CrossRef][Medline] [Order article via Infotrieve]
18. Maheux P, Facchini F, Jeppesen J, Greenfield MS, Clinkingbeard C, Chen YD, Reaven GM. Changes in glucose, insulin, lipid, lipoprotein, and apoprotein concentrations and insulin action in doxazosin-treated patients with hypertension. Comparison between nondiabetic individuals and patients with non-insulin-dependent diabetes mellitus. Am J Hypertens. 1994; 7: 416–424.[Medline] [Order article via Infotrieve]
19. Daae LN, Westlie L. A 5-year comparison of doxazosin and atenolol in patients with mild-to-moderate hypertension: effects on blood pressure, serum lipids, and coronary heart disease risk. Blood Press. 1998; 7: 39–45.[CrossRef][Medline] [Order article via Infotrieve]
20. Simonsen U, Prieto D, Nyborg NC, Mulvany MJ. Effects of doxazosin on functional alterations of isolated coronary arteries from cholesterol-fed rabbits. J Pharm Pharmacol. 1996; 48: 607–614.[Medline] [Order article via Infotrieve]
21. Shaw YJ, Yang YT, Garrison JB, Kyprianou N, Chen CS. Pharmacological exploitation of the 1-adrenoreceptor antagonist doxazosin to develop a novel class of antitumor agents that block intracellular protein kinase B/Akt activation. J Med Chem. 2004; 47: 4453–4462.[CrossRef][Medline] [Order article via Infotrieve]
22. Schaefer EJ, Asztalos BF. Where are we with high-density lipoprotein raising and inhibition of cholesteryl ester transfer for heart disease risk reduction? Curr Opin Cardiol. 2007; 22: 373–378.[CrossRef][Medline] [Order article via Infotrieve]
23. Zannis VI, Chroni A, Krieger M. Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL. J Mol Med. 2006; 84: 276–294.[CrossRef][Medline] [Order article via Infotrieve]
24. Luo Y, Tall AR. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest. 2000; 105: 513–520.[Medline] [Order article via Infotrieve]
25. Miao B, Zondlo S, Gibbs S, Cromley D, Hosagrahara VP, Kirchgessner TG, Billheimer J, Mukherjee R. Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator. J Lipid Res. 2004; 45: 1410–1417.[Abstract/Free Full Text]
26. Major cardiovascular events in hypertensive paitents randomized to doxazosin vs chlorthalidone: the hypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Group. J Am Med Assoc. 2000: 283: 1967–1975.[Abstract/Free Full Text]
27. Tamehiro N, Shigemoto-Mogami Y, Kakeya T, Okuhira KI, Suzuki K, Sato R, Nagao T, Nishimaki-Mogami T. SREBP-2- and LXR-driven dual promoter regulation of hepatic ABCA1 gene expression: mechanism underlying the unique response to cellular cholesterol status. J Biol Chem. 2007. In press.

Related Article:

ATP-Binding Cassette Transporter A1 Gene Transcription Is Downregulated by Activator Protein 2: Doxazosin Inhibits Activator Protein 2 and Increases High-Density Lipoprotein Biogenesis Independent of ₁-Adrenoceptor Blockade

Noriyuki Iwamoto, Sumiko Abe-Dohmae, Makoto Ayaori, Nobukiyo Tanaka, Masatoshi Kusuhara, Fumitaka Ohsuzu, and Shinji Yokoyama
Circ. Res. 2007 101: 156-165. [Abstract] [Full Text] [PDF]

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