Post-Genomic Cardiology

José Marín-García

• Publisher: Academic Press
• Year: 2014
• Print ISBN: 9780124045996
• eBook ISBN: 9780124046429
• Edition: 2
• Topic: Medizin
• Subtopic: Pharmakologie

In this second edition of Post-Genomic Cardiology, developing and new technologies such as translational genomics, next generation sequencing (NGS), bioinformatics, and systems biology in molecular cardiology are assessed in light of their therapeutic potential. As new methods of mutation screening emerge, both for the genome and for the "epigenome, comprehensive understanding of the many mutations that underlie cardiovascular diseases and adverse drug reactions is within our reach.This book, written by respected cardiologist José Marín-García, features discussion on the Hap-Map: the largest international effort to date aiming to define the differences between our individual genomes. This unique reference further reviews and investigates genome sequences from our evolutionary relatives that could help us decipher the signals of genes, and offers a comprehensive and critical evaluation of regulatory elements from the complicated network of the background DNA.- Offers updated discussion of cutting-edge molecular techniques including new genomic sequencing / NGS / Hap-Map / bioinformatics / systems biology approaches- Analyzes mitochondria dynamics and their role in cardiac dysfunction, up-to-date analysis of cardio-protection, and cardio-metabolic syndrome- Presents recent translational studies, gene therapy, transplantation of stem cells, and pharmacological treatments in CVDs

Section III

Post-Genomic Assessment of Coronary Artery Disease, Angiogenesis, and Hypertension

Outline

Chapter 6 Molecular Determinants of Atherosclerosis

Chapter 7 Molecular Genetics of Coronary Artery Disease and Myocardial Infarction

Chapter 8 Cellular and Molecular Aspects of Cardioprotection

Chapter 9 Molecular Determinants of Cardiac Neovascularization

Chapter 10 Post-Genomics Appraisal of Systemic and Pulmonary Hypertension

Chapter 6

Molecular Determinants of Atherosclerosis

Atherosclerosis is a complex disease underlying coronary artery disease (CAD) and stroke, major causes of mortality and morbidity worldwide. Atherosclerosis is currently viewed as a chronic inflammatory disease of the arterial wall that leads to the development of atherosclerotic plaques in the inner lining of the arteries and eventually to thrombosis. Epidemiologic and genome-wide association studies have demonstrated important roles for plasma lipoprotein, blood pressure, diabetes, and other risk factors in the development of this disorder. In most cases, atherosclerosis is caused by a complex interplay of multiple genetic and environmental factors. Over the past decade, important progress in genomics, transcriptomics, proteomics, and lipidomics has provided new insights into the molecular mechanisms underlying the pathogenesis of atherosclerosis. At present, over 160 distinct genes have been shown to contribute to the development and progression of atherosclerosis. A great variety of highly interacting branching signaling and metabolic pathways is implicated in the pathogenesis of this multifaceted disease. Based on attained knowledge, innovative therapeutic strategies have been suggested for the prevention and treatment of this disorder.

Keywords

Atherosclerosis; inflammation; vascular endothelial cells; HDLs; LDLs; oxLDLs; oxidative stress; macrophages; signaling pathways

Overview of Atherogenesis

Atherosclerosis is currently viewed as a chronic inflammatory disease of the arterial wall that leads to the development of atherosclerotic plaques in the inner lining of the arteries and ultimately to the precipitation of acute events.^1–4 It is initiated at predisposed areas, in which slowing blood flow activates the endothelial cells lining the inner arterial surface (Figure 6.1). Activated endothelial cells, resistant to adhesion of leukocytes under normal conditions, increase their permeability and induce expression of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and P- and E-selectins, leading to the capture of leukocytes on their surfaces.^5–8 These changes in the vascular endothelial cells also stimulate the entry and retention of cholesterol-rich low-density lipoprotein (LDL) particles in the vessel wall. Lipoproteins, accumulated in the endothelium and subendothelial extracellular matrix (ECM), undergo various modifications, including aggregation, oxidation, and cleavage, enhancing their proinflammatory potential. Oxidized LDLs (oxLDLs) and oxLDL-derived metabolites as well as proinflammatory cytokines interleukin-1β (IL-1β) and/or tumor necrosis factor α (TNF-α) induce further leukocyte adhesion to the endothelium.

Figure 6.1 Stages in the development of atherosclerotic lesions.
The normal muscular artery and the cell changes that occur during disease progression to thrombosis are shown. a) The normal artery contains three layers. The inner layer, the tunica intima, is lined by a monolayer of endothelial cells that is in contact with blood overlying a basement membrane. In contrast to many animal species used for atherosclerosis experiments, the human intima contains resident smooth muscle cells (SMCs). The middle layer, or tunica media, contains SMCs embedded in a complex extracellular matrix. Arteries affected by obstructive atherosclerosis generally have the structure of muscular arteries. The arteries often studied in experimental atherosclerosis are elastic arteries, which have clearly demarcated laminae in the tunica media, where layers of elastin lie between strata of SMCs. The adventitia, the outer layer of arteries, contains mast cells, nerve endings and microvessels. b) The initial steps of atherosclerosis include adhesion of blood leukocytes to the activated endothelial monolayer, directed migration of the bound leukocytes into the intima, maturation of monocytes (the most numerous of the leukocytes recruited) into macrophages, and their uptake of lipid, yielding foam cells. c) Lesion progression involves the migration of SMCs from the media to the intima, the proliferation of resident intimal SMCs and media-derived SMCs, and the heightened synthesis of extracellular matrix macromolecules such as collagen, elastin and proteoglycans. Plaque macrophages and SMCs can die in advancing lesions, some by apoptosis. Extracellular lipid derived from dead and dying cells can accumulate in the central region of a plaque, often denoted the lipid or necrotic core. Advancing plaques also contain cholesterol crystals and microvessels. d) Thrombosis, the ultimate complication of atherosclerosis, often complicates a physical disruption of the atherosclerotic plaque. Shown is a fracture of the plaque’s fibrous cap, which has enabled blood coagulation components to come into contact with tissue factors in the plaque’s interior, triggering the thrombus that extends into the vessel lumen, where it can impede blood flow. Adapted from Libby et al.³ with permission from Nature Publishing Group.

VCAM-1 preferably binds monocytes and T lymphocytes. Monocytes adhered to the activated endothelium are induced by proinflammatory proteins, chemokines, to infiltrate into the intima, initiating the atherosclerotic plaque. With plaque progression, the recruited monocytes differentiate into tissue macrophages. This central step in atherogenesis is associated with upregulation of expression of scavenger receptors (SRs) and toll-like receptors (TLRs) in the macrophages.^9,10

The macrophages internalize oxLDLs and dead cell fragments via SRs, becoming loaded with modified lipids and oxLDL-derived cholesterol, and are eventually transformed into characteristic foam cells.¹⁰ TLRs bind oxLDLs and pathogen-like molecules and induce a signal cascade, enhancing cell activation.^9,11 Within the inflamed intima, foam cells release various growth factors, cytokines, and reactive oxygen species (ROS), accelerating the inflammatory process.^1,12–14 They also release procoagulant tissue factors and metalloproteinases that contribute to endothelium damage by degrading the arterial ECM.

Upon lesion progression, smooth muscle cells (SMCs) migrate from the media to the intima and proliferate along with resident intimal SMCs. SMCs in the atherosclerotic plaques also internalize LDLs through LDL-related protein-1 (LRP-1) receptors, acquire a prothrombotic phenotype, and release tissue factor. In advancing plaques, macrophages and SMCs can undergo cell death. All these detrimental changes lead to physical disruption of the plaque—plaque rupture—exposing procoagulant plaque’s core to coagulant factors in the blood and initiating thrombosis. Ligands in the ruptured plaques attract platelets and initiate their activation and aggregation, enhancing thrombosis and promoting lesion formation and complications.

Atherosclerosis is a complex polygenic disorder caused by defects in a wide range of unique genes. According to the Mouse Genome Informatics website (www.informatics.jax.org), over 160 distinct genes are listed under the phenotype “Atherosclerotic lesions.” Nevertheless, several single-gene defects have also been described to be associated with dyslipidemia leading to atherosclerosis. A great variety of highly interacting branching signaling and metabolic pathways are implicated in the pathogenesis of this multifaceted disease.¹⁵ In this chapter, we will discuss the major molecular mechanisms and genetic factors that contribute to atherosclerosis.

Lipoproteins

Lipoprotein particles are composed of proteins, lipids (triacylglycerols and phospholipids), and cholesterol. Lipoprotein particles serve to emulsify hydrophobic triacylglycerols and cholesterol and transport them between tissues via the aqueous bloodstream. According to their size and density, lipoproteins can be classified into five major groups (from larger/less dense to smaller/denser): chilomicrons, very low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs), LDLs, and high-density lipoproteins (HDLs).¹⁶ Whereas chilomicrons transport exogenous lipids and cholesterol from the small intestine to peripheral tissues, the other lipoproteins exchange endogenously synthesized lipids between the liver, endothelial cells, adipose, and muscle tissues.

The main source of endogenous triacylglycerols and cholesterol is the liver (Figure 6.2). In the liver, newly synthesized lipids are assembled with apolipoprotein B-100 (ApoB-100) to form VLDLs, which are released into the bloodstream. Here VLDLs receive from HDLs two additional proteins, apolipoproteins C-II and E (ApoC-II and ApoE). ApoC-II is an activator of lipoprotein lipase (LPL) in the vascular endothelial cells. Activation of LPL is a necessary step in the lipid-transportation machinery: LPL-catalyzed hydrolysis of VLDL triacylglycerols releases glycerol and fatty acids, which can th...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Preface
• Section I: Post-Genomic Cardiology
• Section II: Pediatric Cardiology in the Post-Genomic Era
• Section III: Post-Genomic Assessment of Coronary Artery Disease, Angiogenesis, and Hypertension
• Section IV: Post-Genomic Analysis of the Myocardium
• Section V: Heart Failure, Cell Death, and Mitochondria Dynamics
• Section VI: Molecular and Genetic Analysis of Metabolic Disorders
• Section VII: Molecular Genetics of Dysrhythmias
• Section VIII: Genes, Gender, and Epigenetics
• Section IX: Aging and the Cardiovascular System
• Section X: Genetics, Epigenetics, and New Approaches to Treatment
• Section XI: Looking to the Future
• Glossary
• Index