Atherosclerosis: Pathogenesis, Genetics and Experimental Models

Abstract Atherosclerosis is a progressive disease of the arteries that results in the development of heart disease and stroke – the most common causes of death in developed countries and a growing socioeconomic burden in developing countries. Atherosclerosis results from an initial injury to the artery endothelium caused by mechanical and environmental factors, resulting in an inflammatory response in the vessel wall. The location and morphology of the atherosclerotic lesions predict the nature of the resulting vascular disease. Many risk factors for the disease are well known, and current therapies are largely directed at modifying them; however, the large array of poorly understood polygenetic factors affects the development of atherosclerosis. Recent developments in genetic studies have been applied to atherosclerosis and are beginning to rapidly reveal the genetic factors that modulate the pathogenesis of this disease. Key Concepts Atherosclerosis is a common, costly and deadly vascular disease that affects peoples of developed countries and increasingly burdens developing countries. Atherosclerosis is an inflammatory disease of the arterial vascular wall. The pathogenesis of atherosclerosis is complex but is generally explained by the ‘response to injury’ hypothesis for which recent studies in the field extend such hypothesis towards the degree of the inflammatory response to such injury. Atherosclerotic lesions in humans have distinctive morphological characteristics and complications that differ in current animal models, the clinical manifestations correlate mostly with lesion type and location. Both environmental and heritable risk factors modulate atherosclerosis development. Candidate gene and linkage analysis studies have failed to identify previously unknown pathways in the pathogenesis of atherosclerosis. Recent genome‐wide association studies have reproducibly identified several loci involved in the pathogenesis of atherosclerosis, and most of the identified genes are newly implicated in the disease process. Rodent models such as APOE‐ and LDLR‐deficient mice are widely used to study the pathogenesis of atherosclerosis because of its reproducibility and genetic manipulation; however, recent studies with novel and bigger animal models more accurately resemble human disease.