Translating molecular discoveries into new therapies for atherosclerosis

Atherosclerosis is characterized by the thickening of the arterial wall and is the primary cause of coronary artery disease and cerebrovascular disease, two of the most common causes of illness and death worldwide. Clinical trials have confirmed that certain lipoproteins and the renin–angiotensin–aldosterone system are important in the pathogenesis of atherosclerotic cardiovascular disease, and that interventions targeted towards these are beneficial. Furthermore, efforts to understand how risk factors such as high blood pressure, dysregulated blood lipids and diabetes contribute to atherosclerotic disease, as well as to understand the molecular pathogenesis of atherosclerotic plaques, are leading to new targets for therapy.

[1]  C. Gieger,et al.  Genomewide association analysis of coronary artery disease. , 2007, The New England journal of medicine.

[2]  Richard E Gregg,et al.  Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. , 2007, The New England journal of medicine.

[3]  P. Tobias,et al.  Modulation of atherosclerosis in mice by Toll-like receptor 2. , 2005, The Journal of clinical investigation.

[4]  Jayaram Radhakrishnan,et al.  LRP6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors , 2007, Science.

[5]  A. Walsh,et al.  In vivo protection against endotoxin by plasma high density lipoprotein. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Vilmundur Gudnason,et al.  A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction , 2006, Nature Genetics.

[7]  D. Weiss,et al.  Angiotensin II–Induced Hypertension Accelerates the Development of Atherosclerosis in ApoE-Deficient Mice , 2001, Circulation.

[8]  Harlan M Krumholz,et al.  Nonvalidation of reported genetic risk factors for acute coronary syndrome in a large-scale replication study. , 2007, JAMA.

[9]  E. Raines,et al.  Macrophage expression of active MMP-9 induces acute plaque disruption in apoE-deficient mice. , 2005, The Journal of clinical investigation.

[10]  A. Daugherty,et al.  Atherosclerosis and arterial blood pressure in mice. , 2007, Current drug targets.

[11]  Garret A FitzGerald,et al.  Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. , 2005, The Journal of clinical investigation.

[12]  S. Narumiya,et al.  Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice , 2004 .

[13]  D. Rader Illuminating HDL--is it still a viable therapeutic target? , 2007, The New England journal of medicine.

[14]  D. Gudbjartsson,et al.  Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. , 2005, Journal of the American Medical Association (JAMA).

[15]  Yuzhi Zhang,et al.  Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. , 2005, The Journal of clinical investigation.

[16]  Alexander Pertsemlidis,et al.  Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9 , 2005, Nature Genetics.

[17]  T. Littlewood,et al.  Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis , 2006, Nature Medicine.

[18]  D. Rader,et al.  COX-2-Derived Prostacyclin Confers Atheroprotection on Female Mice , 2004, Science.

[19]  Jonathan C. Cohen,et al.  Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. , 2006, The New England journal of medicine.

[20]  Jonathan C. Cohen,et al.  A Common Allele on Chromosome 9 Associated with Coronary Heart Disease , 2007, Science.

[21]  K. Mossman The Wellcome Trust Case Control Consortium, U.K. , 2008 .

[22]  Dolores Corella,et al.  Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans , 2008, Nature Genetics.

[23]  J. Breslow,et al.  Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mices⃞s⃞ The online version of this article (available at http://www.jlr.org) contains one supplemental table. Published, JLR Papers in Press, August 1, 2003. DOI 10.1194/jlr.M300203-JLR200 , 2003, Journal of Lipid Research.

[24]  S. Gordon Macrophage heterogeneity and tissue lipids. , 2007, The Journal of clinical investigation.

[25]  P. Davies Endothelial mechanisms of flow-mediated athero-protection and susceptibility. , 2007, Circulation research.

[26]  S. Yusuf,et al.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. , 2000 .

[27]  D. Gudbjartsson,et al.  Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial. , 2005, JAMA.

[28]  R. Virmani,et al.  Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[29]  D. Rader,et al.  ABC1: connecting yellow tonsils, neuropathy, and very low HDL. , 1999, The Journal of clinical investigation.

[30]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[31]  A. Tall,et al.  ATP-binding cassette transporters G 1 and G 4 mediate cellular cholesterol efflux to high-density lipoproteins , 2004 .

[32]  M. Cybulsky,et al.  A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. , 2001, The Journal of clinical investigation.

[33]  Jilly F. Evans,et al.  The 5-lipoxygenase pathway promotes pathogenesis of hyperlipidemia-dependent aortic aneurysm , 2004, Nature Medicine.

[34]  Aldons J Lusis,et al.  Thematic review series: The Pathogenesis of Atherosclerosis Published, JLR Papers in Press, April 1, 2004. DOI 10.1194/jlr.R400001-JLR200 The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL , 2004, Journal of Lipid Research.

[35]  Kari Stefansson,et al.  A common variant on chromosome 9p21 affects the risk of myocardial infarction. , 2007, Science.

[36]  S. Akira,et al.  Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[37]  G. Davı̀,et al.  Platelet activation and atherothrombosis. , 2007, The New England journal of medicine.

[38]  P. Libby,et al.  Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. , 2007, The Journal of clinical investigation.

[39]  S. Narumiya,et al.  Roles of thromboxane A(2) and prostacyclin in the development of atherosclerosis in apoE-deficient mice. , 2004, The Journal of clinical investigation.

[40]  Erling Falk,et al.  Plaque rupture in humans and mice. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[41]  S. Hajduk,et al.  Human High Density Lipoproteins Are Platforms for the Assembly of Multi-component Innate Immune Complexes* , 2005, Journal of Biological Chemistry.

[42]  A. Zernecke,et al.  SDF-1alpha-mediated tissue repair by stem cells: a promising tool in cardiovascular medicine? , 2006, Trends in cardiovascular medicine.

[43]  Colin Berry,et al.  Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. , 2007, JAMA.

[44]  D. Rader,et al.  The adhesion receptor CD44 promotes atherosclerosis by mediating inflammatory cell recruitment and vascular cell activation. , 2001, The Journal of clinical investigation.

[45]  A. Tall,et al.  ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[46]  A. Zalewski,et al.  Role of lipoprotein-associated phospholipase A2 in atherosclerosis and its potential as a therapeutic target. , 2006, Current opinion in pharmacology.

[47]  H. C. Stary,et al.  Natural history and histological classification of atherosclerotic lesions: an update. , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[48]  M. Reilly,et al.  Pharmacological Activation of Liver X Receptors Promotes Reverse Cholesterol Transport In Vivo , 2005, Circulation.

[49]  S. Mane,et al.  LRP 6 Mutation in a Family with Early Coronary Disease and Metabolic Risk Factors , 2008 .

[50]  K. Michelsen,et al.  Toll-like receptor signaling and atherosclerosis , 2006, Current opinion in hematology.

[51]  P. Barter,et al.  Antiinflammatory Properties of HDL , 2004 .

[52]  F. Tacke,et al.  Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. , 2007, The Journal of clinical investigation.

[53]  J. Weissenbach,et al.  Mutations in PCSK9 cause autosomal dominant hypercholesterolemia , 2003, Nature Genetics.

[54]  Aldons J. Lusis,et al.  Atherosclerosis : Vascular biology , 2000 .

[55]  P. Libby,et al.  Lysosomal Cysteine Proteases in Atherosclerosis , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[56]  T. Kooistra,et al.  Mouse models for atherosclerosis and pharmaceutical modifiers. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[57]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[58]  J. Gulcher,et al.  The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke , 2004, Nature Genetics.

[59]  E. Brilakis,et al.  Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. , 2005, The New England journal of medicine.

[60]  N. Webb Secretory phospholipase A2 enzymes in atherogenesis , 2005, Current opinion in lipidology.

[61]  Anders Gabrielsen,et al.  Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[62]  D. Rader,et al.  Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. , 2007, The Journal of clinical investigation.

[63]  S. Reddy,et al.  Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention , 2006, Nature Clinical Practice Cardiovascular Medicine.

[64]  L. Peltonen,et al.  Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1) , 2004, Nature Genetics.

[65]  C. Funk Leukotriene modifiers as potential therapeutics for cardiovascular disease , 2005, Nature Reviews Drug Discovery.

[66]  C. Jackson Defining and defending murine models of plaque rupture. , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[67]  F. Tacke,et al.  Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[68]  S. Bornstein,et al.  Toll-like receptors, endocrine stress response, and arteriosclerosis. , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[69]  A. Prat,et al.  NARC-1/PCSK9 and Its Natural Mutants , 2004, Journal of Biological Chemistry.

[70]  E. Topol,et al.  Protein carbamylation links inflammation, smoking, uremia and atherogenesis , 2007, Nature Medicine.

[71]  I. Tabas Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis: The Importance of Lesion Stage and Phagocytic Efficiency , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[72]  Eric Boerwinkle,et al.  Sequence Variations in PCSK 9 , Low LDL , and Protection against Coronary Heart Disease , 2006 .

[73]  J. Griffin,et al.  Endothelial and antithrombotic actions of HDL. , 2006, Circulation research.

[74]  D. Grainger TGF-β and atherosclerosis in man , 2007 .

[75]  E. Falk,et al.  Smooth Muscle Cells in Atherosclerosis Originate From the Local Vessel Wall and Not Circulating Progenitor Cells in ApoE Knockout Mice , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[76]  Jonathan C. Cohen,et al.  Autosomal Recessive Hypercholesterolemia Caused by Mutations in a Putative LDL Receptor Adaptor Protein , 2001, Science.

[77]  K. Moore,et al.  Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways , 2004, Nature Medicine.

[78]  A. Lusis,et al.  Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. , 2004, The New England journal of medicine.

[79]  M. Makuuchi,et al.  Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis , 2002, Nature Medicine.

[80]  C. Daige,et al.  Macrophage Liver X Receptor Is Required for Antiatherogenic Activity of LXR Agonists , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[81]  D. Rader,et al.  Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. , 2004, The New England journal of medicine.

[82]  P. Kovanen Mast cells: multipotent local effector cells in atherothrombosis , 2007, Immunological reviews.

[83]  E. Fisher,et al.  Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[84]  D. Broide,et al.  IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. , 2004, The Journal of clinical investigation.

[85]  M. Caulfield,et al.  Effects of torcetrapib in patients at high risk for coronary events. , 2007, The New England journal of medicine.

[86]  A. Newby,et al.  Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. , 2005, Physiological reviews.

[87]  A. Zeiher,et al.  Vascular repair by circulating endothelial progenitor cells: the missing link in atherosclerosis? , 2004, Journal of Molecular Medicine.

[88]  E. Puré,et al.  Deletion of microsomal prostaglandin E synthase-1 augments prostacyclin and retards atherogenesis , 2006, Proceedings of the National Academy of Sciences.

[89]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[90]  Subramaniam Pennathur,et al.  Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. , 2007, The Journal of clinical investigation.

[91]  G. O'neill,et al.  Antagonism of the prostaglandin D2 receptor 1 suppresses nicotinic acid-induced vasodilation in mice and humans. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[92]  G. Ertl,et al.  Mechanisms of Disease: Toll-like receptors in cardiovascular disease , 2007, Nature Clinical Practice Cardiovascular Medicine.

[93]  Stanley L Hazen,et al.  ATVB in Focus Redox Mechanisms in Blood Vessels , 2005 .

[94]  A Daugherty,et al.  Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice. , 2000, The Journal of clinical investigation.

[95]  Alberto Mantovani,et al.  Macrophage activation and polarization. , 2008, Frontiers in bioscience : a journal and virtual library.

[96]  A. Lusis,et al.  Identification of 5-Lipoxygenase as a Major Gene Contributing to Atherosclerosis Susceptibility in Mice , 2002, Circulation research.

[97]  Jonathan C. Cohen,et al.  Molecular biology of PCSK9: its role in LDL metabolism. , 2007, Trends in biochemical sciences.

[98]  M. Krieger,et al.  Loss of SR-BI Expression Leads to the Early Onset of Occlusive Atherosclerotic Coronary Artery Disease, Spontaneous Myocardial Infarctions, Severe Cardiac Dysfunction, and Premature Death in Apolipoprotein E-Deficient Mice , 2002, Circulation research.

[99]  J. Witztum,et al.  Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL , 2003, Nature Medicine.

[100]  C. Reardon,et al.  The unusual suspects: an overview of the minor leukocyte populations in atherosclerosis , 2005 .

[101]  Douglas T. Golenbock,et al.  Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages , 2006, Proceedings of the National Academy of Sciences.

[102]  J. Kastelein,et al.  Potent Reduction of Apolipoprotein B and Low-Density Lipoprotein Cholesterol by Short-Term Administration of an Antisense Inhibitor of Apolipoprotein B , 2006, Circulation.

[103]  M. Cybulsky,et al.  Getting to the site of inflammation: the leukocyte adhesion cascade updated , 2007, Nature Reviews Immunology.

[104]  D. Rader Molecular regulation of HDL metabolism and function: implications for novel therapies. , 2006, The Journal of clinical investigation.

[105]  R. Hammer,et al.  Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[106]  T. Willson,et al.  Synthetic LXR ligand inhibits the development of atherosclerosis in mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[107]  Paul Schoenhagen,et al.  Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. , 2003, JAMA.