Lipid lowering improves endothelial functions.
The healthy endothelium usually provides an anticoagulant, vasodilatory and anti-inflammatory spectrum of functions that are central in vascular homeostasis. Dysfunction of the endothelium is a common feature of all phases of atherosclerosis. Hypercholesterolemia provokes many aspects of endothelial dysfunction before and during the development of atheroma. For example, a high cholesterol diet leads to the formation of a fatty streak and the recruitment and binding of blood leukocytes to the artery wall. This process requires expression by the endothelial cells of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). In rabbits that are fed an atherogenic diet, the aortic endothelium, which usually expresses little VCAM-1, shows foci of VCAM-1 expression soon after initiating this diet. Furthermore, lowering plasma cholesterol by diet or drugs down-regulates the expression of VCAM-1 and reduces the density of inflammatory cells in the atherosclerotic plaque. Hypercholesterolemia also attenuates normal vasodilatation to several stimuli such as exercise and acetylcholine. In healthy subjects, the vascular endothelium produces the vasodilator nitric oxide. In atherosclerosis, however, nitric oxide bioavailability is impaired. As a result, atherosclerotic coronary arteries commonly display a vasoconstrictor response when challenged with acetylcholine. Lipid lowering appears to favorably influence endothelial vasomotor and inflammatory functions in ways that may benefit patients with coronary artery disease. Continued probing of the basic mechanisms of endothelial dysfunction and its treatment may lead to new therapies that offer clinical benefits in patients with atherosclerosis, including reductions in coronary events.
Libby
P
P
Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, LMRC 307, Boston, MA 02115, USA. plibby@bustoff.bwh.harvard.edu
Aikawa
M
M
Kinlay
S
S
Selwyn
A
A
Ganz
P
P
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy / Q000503:physiopathology; D003327:Coronary Disease / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000502:physiology*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D050356:Lipid Metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011817:Rabbits; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000960:Hypolipidemic Agents; D019010:Vascular Cell Adhesion Molecule-1; D009569:Nitric Oxide