THE RESPONSE-TO-RETENTION HYPOTHESIS OF ATHEROGENESIS REINFORCED

Many lines of evidence indicate that the key initiating event in early atherosclerosis is the subendothelial retention of cholesterol-rich, atherogenic lipoproteins. Once retained, these lipoproteins provoke a cascade of responses that lead to disease in a previously non-lesional artery. We review recent experimental work that has substantially rei nforced this hypothesis. Lipoprotein retention has been shown to be a pivotal requirement in the murine model of atherosclerosis: low-densit y lipoprotein, engineered through site-directed mutagenesis of apolipo protein-B-100 to bind poorly to arterial proteoglycans, causes relativ ely few lesions in vivo, even during significant hyperlipidemia. In ad dition, many molecules in the arterial wall that are involved in the r etention of atherogenic lipoproteins and in arterial responses to reta ined material have recently been characterized. Overall, the response- to-retention hypothesis can now be regarded as a central paradigm in o ur understanding of the pathogenesis of this deadly disease. Curr Opin Lipidol 9:471-474. (C) 1998 Lippincott Williams & Wilkins