Genetically-engineered animals as research models for atherosclerosis: their use for the characterization of PPAR agonists in the treatment of cardiometabolic disorders.

摘要

Experimental approaches to understand the pathogenesis and to develop treatments of atherosclerosis involve studies in animal and cellular models. However, relevant animal models are rare since atherosclerosis is a disease that naturally affects only humans and one or two other species (pigs and certain primates). For a long time, atherosclerosis studies were carried out using diet-induced atherosclerosis models, even though the diets were unphysiological and the arterial lesions that developed were often limited in size, composition and location. During the last decade, with the advent of molecular genetics and genetic manipulation techniques, the development of genetically-engineered animals, mainly mice, allowed an explosion in the number of models resulting in a tremendous progress in atherosclerosis research and enhancement of our understanding of the disease. Atherosclerosis is a multifactorial disease which normally develops very slowly and asymptomatically during several decades, leading to atheromatous plaque formation. Once the plaque is weakened, its rupture or erosion induces severe clinical complications, such as myocardial infarction or cerebrovascular accidents. Several risk factors predispose to atherosclerosis including hypertension and abnormalities in lipoprotein metabolism and glucose homeostasis. The formation of the atherosclerotic lesion is a complex process, characterized by the presence of lipid-laden monocyte-derived macrophages (called foam cells), establishing therefore a status of chronic inflammation. The dysregulated expression of genes encoding proteins involved in the control of metabolic pathways contributes to vascular inflammation and the development of atherosclerosis. The expression of these genes is controlled by different transcription factors amongst which are the Peroxisome Proliferator-Activated Receptor (PPAR) family of nuclear receptors. This review focuses on the use of genetically-engineered animals as models for experimental atherosclerosis research, pointing out their contribution to investigate the implication of PPARs and their ligands in regulating metabolic and inflammatory abnormalities predisposing to atherosclerosis development.