Heat shock proteins, inflammation, and cardiovascular disease.

Abstract

Atherosclerosis and its associated complications, such as coronary artery disease, peripheral vascular disease, and stroke, are the leading causes of morbidity and mortality in all racial groups of most westernized societies. A better understanding of the events that lead to the induction and progression of atherosclerosis and the development of strategies that control these processes would have a significant impact on human health. Atherosclerosis is a chronic inflammatory condition that usually begins at an early age in the absence of lipid accumulation, with fatty streaks composed of lipid-laden macrophages (foam cells) developing at later stages. T lymphocytes, predominantly of the CD4+ phenotype, are associated with the intima layer of the vessel. The inflammatory process at atherogenic sites leads to the production of cytokines and other inflammatory mediators, resulting in cell migration, proliferation, extracellular matrix production, and plaque development.1–3⇓⇓ Monocytes and macrophages appear intimately involved with the development of atherosclerosis; mice with the osteopetrotic ( op ) mutation in the macrophage colony-stimulating factor (M-CSF) gene, which results in a complete absence of M-CSF in the serum and tissues and a marked reduction in the number of circulating monocytes, exhibit significantly less atherosclerosis than control littermates when bred into an apolipoprotein (apo) E–deficient background,.4 The precise role of T and B cells in atherosclerosis remains unclear. Although activated T cells are a dominant feature of atherosclerotic lesions,5,6⇓ studies demonstrating that atherosclerosis can be induced by hypercholesterolemia in mice deficient in T and B cells suggest that these cells are not essential.7–9⇓⇓ However, the cholesterol levels in these studies far exceeded those present in human subjects without any genetic defect, and the findings should therefore be interpreted with caution. Indeed, other evidence indicates that T cells may attenuate atherogenesis by some means, because the elimination of …