eBriefing

Moving a Mountain: New Targets for Atherosclerosis Treatment

Moving a Mountain
Reported by
Catherine Zandonella

Posted June 17, 2008

Overview

Coronary heart disease resulting from atherosclerosis, the buildup of complex plaques composed of fatty and fibrous material in artery walls, is the number one cause of death among Americans. The buildup commences as early as childhood or adolescence, and after years of growth, the plaques can rupture and block blood flow to the heart, brain, legs, or other parts of the body. Often, a heart attack or stroke is the first indication that a person suffers from atherosclerosis.

Atherosclerosis can be managed via lifestyle changes or statin drugs, which inhibit cholesterol synthesis and upregulate LDL receptors in the liver. However, researchers would like to improve upon current treatments using new strategies, such as raising good cholesterol (HDL) levels and blocking the inflammatory response. Possible approaches discussed at an April 22, 2008, meeting at the Academy include leukotriene inhibition, promotion of peroxisome proliferator-activated receptor (PPAR) agonists, and blocking the action of the peptide hormone angiotensin II.

Web Sites

American Heart Association
Provides information about how to prevent and treat heart disease.

CV Therapeutics
A biopharmaceutical company primarily focused on the discovery, development and commercialization of new small molecule drugs for the treatment of cardiovascular diseases.

Gill Heart Institute, University of Kentucky
The Web site of the Gill Heart Institute includes a Cardiovascular Media Library, as well as information about procedures such as cardiac catheterization and echocardiogram.

Lipids Online
An educational resource that provides information about cholesterol and atherosclerosis.


Journal Articles

Alan Daugherty

Daugherty A, Cassis LA. 2007. Commentary. Angiotensin converting enzyme inhibitors and aortic rupture: population based case control study. Perspect. Vasc. Surg. Endovasc. Ther. 19: 342-344.

Henriques T, Zhang X, Yiannikouris FB, Daugherty A, Cassis LA. 2008. Androgen increases AT1a receptor expression in abdominal aortas to promote angiotensin II-induced AAAs in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. May 1. [Epub ahead of print]

Rader DJ, Daugherty A. 2008. Translating molecular discoveries into new therapies for atherosclerosis. Nature 451: 904-913.

Lu H, Boustany-Kari CM, Daugherty A, Cassis LA. 2007. Angiotensin II increases adipose angiotensinogen expression. Am. J. Physiol. Endocrinol. Metab. 292: E1280-E1287. Full Text

Lu H, Rateri DL, Feldman DL, Jr et al. 2008. Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice. J. Clin. Invest. 118: 984-993. Full Text

Colin Funk

Jiang W, Hall SR, Moos MP, et al. 2008. Endothelial cysteinyl leukotriene 2 receptor expression mediates myocardial ischemia-reperfusion injury. Am. J. Pathol. 172: 592-602.

Lötzer K, Jahn S, Kramer C, et al. 2007. 5-Lipoxygenase/cyclooxygenase-2 cross-talk through cysteinyl leukotriene receptor 2 in endothelial cells. Prostaglandins Other Lipid Mediat. 84: 108-115.

Cao RY, Adams MA, Habenicht AJ, Funk CD. 2007. Angiotensin II-induced abdominal aortic aneurysm occurs independently of the 5-lipoxygenase pathway in apolipoprotein E-deficient mice. Prostaglandins Other Lipid Mediat. 84: 34-42.

Doepping S, Funk CD, Habenicht AJ, Spanbroek R. 2007. Selective 5-lipoxygenase expression in Langerhans cells and impaired dendritic cell migration in 5-LO-deficient mice reveal leukotriene action in skin. J. Invest. Dermatol. 127: 1692-1700. Epub 2007 Mar 29.

Funk CD. Lipoxygenase pathways as mediators of early inflammatory events inatherosclerosis. 2006. Arterioscler. Thromb. Vasc. Biol. 26: 1204-1206. Full Text

Richard Lawn

Huby T, Afzal V, Doucet C, et al. 2003. Regulation of the expression of the apolipoprotein(a) gene: evidence for a regulatory role of the 5′ distal apolipoprotein(a) transcription control region enhancer in yeast artificial chromosome transgenic mice. Arterioscler. Thromb. Vasc. Biol. 23: 1633-1639. Full Text

Kathiresan S, Melander O, Guiducci C, et al. 2008. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nature Genetics 40: 189-197.

Marson A, Lawn RM, Mikita T. 2004. Oxidized low density lipoprotein blocks lipopolysaccharide-induced interferon beta synthesis in human macrophages by interfering with IRF3 activation. J. Biol. Chem. 279: 28781-28788. Full Text

Morello F, de Boer RA, Steffensen KR, et al. 2005. Liver X receptors alpha and beta regulate renin expression in vivo. J. Clin. Invest. 115: 1913-1922. Full Text

Schneider M, Witztum JL, Young SG, et al. 2005. High-level lipoprotein [a] expression in transgenic mice: evidence for oxidized phospholipids in lipoprotein [a] but not in low density lipoproteins. J. Lipid Res. 46: 769-778. Full Text

Rajendra K. Tangirala

Blaschke F, Takata Y, Caglayan E, et al. 2006. A nuclear receptor corepressor-dependent pathway mediates suppression of cytokine-induced C-reactive protein gene expression by liver X receptor. Circ. Res. 99: e88-99. Full Text

Bradley MN, Hong C, Chen M, et al. 2007. Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. J. Clin. Invest. Aug;117: 2337-2346. Full Text

Takata Y, Chu V, Collins AR, et al. 2005. Transcriptional repression of ATP-binding cassette transporter A1 gene in macrophages: a novel atherosclerotic effect of angiotensin II. Circ. Res. 97: e88-e96. Full Text

Takata Y, Liu J, Yin F, et al. 2008. PPARdelta-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis. Proc. Natl. Acad. Sci. USA 105: 4277-4282.

Tangirala RK, Bischoff ED, Joseph SB, et al. 2002. Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc. Natl. Acad. Sci. USA 99: 11896-11901. (PDF, 556 KB) Full Text

Tangirala RK, Tsukamoto K, Chun SH, et al. 1999. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation 100: 1816-1822. Full Text

Speakers

Colin D. Funk, PhD

Queen's University
e-mail | web site | publications

Colin Funk is a professor in the Departments of Physiology and Biochemistry in the Faculty of Health Sciences at Queen's University in Kingston, Ontario. He is also serving as the Canada Research Chair in Molecular, Cellular, and Physiological Medicine and career investigator of the Heart and Stroke Foundation of Canada until 2011. Prior to his position at Queen's University, Funk was an associate professor in the Department of Pharmacology at Vanderbilt University in Nashville and as a professor of Pharmacology at the University of Pennyslvania School of Medicine.

Funk received his PhD in experimental medicine from McGill University in Montreal. He was a postdoctoral fellow in the laboratory of Bengt Samuelsson in the Department of Physiological Chemistry at the Karolinksa Institutet in Stockholm.

Alan Daugherty, PhD

University of Kentucky College of Medicine
Cardiovascular Research Center
e-mail | web site | publications

Born in Liverpool, England, Alan Daugherty's educational training is in pharmacology. He earned a bachelor's degree from Sunderland Polytechnic, and post-doctorate and doctor of science degrees from University of Bath.

He serves as principal investigator on numerous NIH-funded research initiatives, as well as sponsor and co-investigator on many NIH- and American Heart Association-funded projects. Daugherty's research concentrates on the role of angiotensin peptides in the development of atherosclerosis and abdominal aortic aneurysms. His funded research initiatives currently total more than $28 million.

Daugherty provides volunteer-service to the American Heart Association, serving in numerous capacities including chair of the Arteriosclerosis, Thrombosis and Vascular Biology Council; the American Diabetes Association, and the International Atherosclerosis Society.

A recognized medical scholar, he has published six books, 98 manuscripts, 12 book chapters, 35 invited reviews, and four educational publications.

Richard M. Lawn, PhD

CV Therapeutics, Inc
e-mail | web site | publications

Richard Lawn received his BA in astronomy from Harvard College in 1969 and his PhD in molecular, cellular, and developmental biology from the University of Colorado in 1977. Lawn is considered one of the pioneers in the field of cloning and expressing human genes. As a postdoctoral fellow in the laboratory of Tom Maniatis at CalTech, he constructed the first human genomic DNA clone library and characterized the human beta globin gene locus, the first human genes so isolated.

Lawn has served as senior scientist and staff scientist at Genentech, Inc., from 1980–1990, as professor of medicine at Stanford from 1990–1998 and as vice president, discovery research at CV Therapeutics, Inc. from 1998 to the present.

He has cloned a number of genes involved in coagulation and heart disease, including the globin genes, serum albumin, anti-thrombin III, tissue factor, lipoprotein lipase, lecithin cholesterol acyl transferase, cholesteryl ester transfer protein, apolipoprotein(a) and anti-hemophilia factor VIII. Subsequent to his role in identifying ABCA1 as the defective gene in Tangier disease, he has been seeking to discover a therapeutic approach to increase reverse cholesterol transport and HDL cholesterol to reduce cardiovascular disease.

Lawn received the Dr. Murray Thelin Award in 1989 and the Distinguished Inventor Award from the Intellectual Property Owner's Association in 1999 for his role in the development of recombinant factor VIII.

Rajendra K. Tangirala, PhD

David Geffen School of Medicine at UCLA
e-mail | publications

Rajendra Tangirala is an assistant professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles. He is also director of the Mouse Phenotyping Core and co-director of the Inflammation Core at the UCLA/UCSD Diabetes Endocrinology Research Center.

Tangirala received his PhD from the Medical College of Pennsylvania and was a postdoctoral fellow at the University of California, San Diego School of Medicine and the University of Pennsylania Medical Center. Prior to his position at UCLA, Tangirala was on the research faculty in the Departments of Cardiovascular Medicine and Experimental Therapeutics from 1997–2000. From 2000–2003 he was a leader and research scientist II at X-Ceptor Therapeutics, Inc., in San Diego, CA.

Tangirala is the recipient of numerous honors and awards including the International Atherosclerosis Society's Young Investigator Award for Scientific Excellence and the Scientist Development Award from the American Heart Association.


Catherine Zandonella

Catherine Zandonella is a science writer based in New York City, covering such topics as environmental science, public health, and applied technology. She has a master's degree in public health from the University of California, Berkeley. Zandonella has written for a number of publications, including New Scientist, The Scientist, and Nature.