Atherosclerosis: Pathogenesis, Genetics and Experimental Models

Atherosclerosis is a disease of the arteries that results in heart disease and stroke – the most common causes of death in developed countries, and a growing burden in developing countries. Atherosclerosis results from injury to the artery endothelium caused by mechanical and environmental factors, and the resulting inflammatory response in the vessel wall. The location and morphology of the atherosclerotic lesions predict the nature of the resulting vascular disease. Some risk factors for the disease are well known and current therapies are largely directed at modifying them, but the tendency to develop atherosclerosis is determined largely by polygenetic factors that are poorly understood. 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. Atherosclerotic lesions have varied morphology, and clinical manifestations correlate 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 publication of the HapMap has made possible genome-wide association studies aimed at probing 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. APOE- or LDLR-deficient mice are widely used models to study the pathogenesis of atherosclerosis. Keywords: atheroma; atherosclerosis; coronary artery disease; endothelial dysfunction; foam cell; hyperlipidaemia; hypertension; myocardial infarct; stroke; vascular inflammation