Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation.

Abstract

IntroductionExcess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) The vascular endothelium is important in the maintenance of vascular homeostasis. Normally, the vascular endothelium prevents inappropriate vasospasm and platelet adhesion to the vascular surface through the production of numerous paracrine factors (for review see reference 1). Principal among these mediators of vascular homeostasis is endothelium-derived relaxing factor (EDRF),' an endothelial product that has been identified as nitric oxide (NO) (2), or a closely related redoxactivated form of NO (3). This endothelial product relaxes vascular smooth muscle and prevents platelet adhesion to the endothelial surface through a cyclic 3 ',5 '-guanosine monophosphate-mediated mechanism (4, 5). Abnormalities in EDRF action have been described in association with known risk factors for acute vascular events including hypercholesterolemia (6) and atherosclerosis (7). These abnormalities develop early in the course of vascular disease (6,8) and may participate in the development of clinically significant vascular events.There are now several lines of evidence linking excess vascular oxidative stress to the impairment of EDRF action associated with hypercholesterolemia and atherosclerosis. Early in atherogenesis, LDL becomes entrapped in the subendothelial space of lesion-prone arterial sites where it is subject to oxidation by endothelial cells (9), smooth muscle cells (10), and resident monocyte/macrophages (11). Oxidized LDL (ox-LDL) inhibits receptor-mediated endothelium-dependent arterial relaxation (12) and signal transduction (13). Moreover, ox-LDL is cytotoxic (14)

Action of probucol in arteries from normal and hypercholesterolaemic rabbits

“…(Parthasarathy et al, 1986) and recently it has been reported that dietary probucol and other antioxidants prevent the inhibition of endothelium-dependent relaxation in aorta from cholesterol-fed rabbits (Simon et al, 1993;Keaney et al, 1995) high-K+ depo-as well as in human subjects (Plane et al, 1993 …”

Ultrastructural Localization of Secretory Type II Phospholipase A 2 in Atherosclerotic and Nonatherosclerotic Regions of Human Arteries

“…26,27 The concentration of lyso-PC in the atherosclerotic aorta has been reported to be higher and the PC to lyso-PC ratio lower than in comparable control tissue in rabbits. 28 Previous immunolocalization studies from our laboratory showed the presence of snpPLA 2 associated with SMCs in normal human arterial media and in the intima-media of atherosclerotic arteries. 29 These results agree with those of other groups, indicating that SMCs are an important source of snpPLA 2 .…”

Hydrogen Peroxide Activates Endothelial Nitric-oxide Synthase through Coordinated Phosphorylation and Dephosphorylation via a Phosphoinositide 3-Kinase-dependent Signaling Pathway

“…With regard to the former, superoxide combines readily with NO in a diffusion-limited reaction (k ϭ 1.9 ϫ 10 10 M Ϫ1 ⅐s Ϫ1 ; Ref. 19), and this process is well known with respect to its role in limiting the bioactivity of endotheliumderived NO in the setting of vascular disease (20,21).…”