Reduced Endothelial Nitric Oxide Synthase Expression and Production in Human Atherosclerosis

Abstract

Background-NO regulates vascular tone and structure, platelets, and monocytes. NO is synthesized by endothelial NO synthase (eNOS). Endothelial dysfunction occurs in atherosclerosis. Methods and Results-With a porphyrinic microsensor, NO release was measured in atherosclerotic human carotid arteries and normal mammary arteries obtained during surgery. eNOS protein expression was analyzed by immunohistochemistry. In normal arteries, the initial rate of NO release after stimulation with calcium ionophore A23187 (10 mol/L) was 0.42Ϯ0.05 (mol/L)/s (nϭ10). In contrast, the initial rate of NO release was markedly reduced in atherosclerotic segments, to 0.08Ϯ0.04 (mol/L)/s (nϭ10, PϽ0.0001). NO peak concentration in normal arteries was 0.9Ϯ0.09 mol/L (nϭ10) and in atherosclerotic segments, 0.1Ϯ0.03 mol/L (nϭ10, PϽ0.0001). Reduced NO release in atherosclerotic segments was accompanied by marked reduction of immunoreactive eNOS in luminal endothelial cells, although specific endothelial cell markers (CD31) were present (nϭ13). Endothelial cells of vasa vasorum of atherosclerotic segments, however, remained positive for eNOS, as was the endothelium of normal arteries. Conclusions-In clinically relevant human atherosclerosis, eNOS protein expression and NO release are markedly reduced. This may be involved in the progression of atherosclerosis. (Circulation. 1998;97:2494-2498.)

GDF11 Protects against Endothelial Injury and Reduces Atherosclerotic Lesion Formation in Apolipoprotein E-Null Mice

“…Nitric oxide (NO), produced by eNOS, plays a pivotal role in regulating endothelial cell function, apoptosis, and exhibits athero-protective effects. 25,26 Accordingly, AAV-GDF11 and GDF11 treatments significantly increased the NO levels compared with the AAV-GFP or vehicle groups (see Supplementary Figure S8a), which are consistent Data were shown as mean ± SD. Analysis of variance (ANOVA) followed by LSD t-test was used to compare the differences among different groups.…”

Endothelial arginase: A new target in atherosclerosis

“…Although our understanding of biochemical regulation of endothelial NO bioactivity has remarkably advanced on various levels of eNOS gene expression-eNOS enzymatic activity to degradation of NO [7]-no single mechanism can fully explain endothelial dysfunction in atherosclerosis. Initial studies suggest that endothelial dysfunction in atherosclerosis is due to a decrease in eNOS gene expression [8]. Research in more recent years, however, provides evidence suggesting that reduced NO bioavailability, mainly due to a decrease in eNOS enzymatic activity rather than eNOS gene expression and accelerated inactivation of NO by oxidative stress, is the central mechanism of endothelial dysfunction in atherosclerosis [9].…”

Ambulatory blood pressure, left ventricular mass and vascular phenotypes in relation to the endothelial nitric oxide synthase gene Glu298Asp and intron 4 polymorphisms in a population-based family study

“…4 Furthermore, it has been shown that NO release and synthesis are decreased in patients with atherosclerosis. 5 The endothelium-derived NO is significantly involved in the regulation of vascular wall tone. 6 Disruption of the gene encoding eNOS in mice results in the development of arterial hypertension, 7 and humans with hypertension have been found to have impaired NO synthesis.…”