Expression of Multiple Isoforms of Nitric Oxide Synthase in Normal and Atherosclerotic Vessels

Abstract

Atherosclerosis is associated with reduced endothelium-derived relaxing factor bioactivity. To determine whether this is due to decreased synthesis of nitric oxide synthase (NOS), we examined normal and atherosclerotic human vessels by in situ hybridization and immunocytochemistry by using probes specific for endothelial (ecNOS), inducible (iNOS), and neuronal (nNOS) NOS isoforms, ecNOS was detected in endothelial cells overlying normal human aortas, fatty streaks, and advanced atherosclerotic lesions. A comparison of the relative expression of ecNOS to von Willebrand factor on serial sections of normal and atherosclerotic vessels indicated that there was a decrease in the number of endothelial cells expressing ecNOS in advanced lesions. iNOS and nNOS were not detected in normal vessels, but widespread production of these isoforms was found in early and advanced lesions associated with macrophages, endothelial cells, and mesenchymal-appearing intimal cells. These data suggest that there is (1) a loss of ecNOS expression by endothelial cells over advanced atherosclerotic lesions and (2) a significant increase in overall NOS synthesis by other cell types in advanced lesions composed of the ecNOS, nNOS, and iNOS isoforms. We hypothesize that the increased expression of NOS and presumably NO in atherosclerotic plaques may be related to cell death and necrosis in these tissues.

Endothelial arginase: A new target in atherosclerosis

“…This conclusion is supported by most studies of atherosclerotic animal models, showing an unchanged or even augmented protein level of eNOS in atherosclerotic arteries, despite the presence of endothelial dysfunction [10-12,13••]. Moreover, studies with human aortic and coronary arterial tissues obtained from autopsy or from transplant donors found only a significantly deceased eNOS gene expression in endothelial cells in advanced but not early atherosclerotic lesions [14,15]. Most recently, a study with human coronary atherectomy specimens showed a higher eNOS gene expression in patients with acute coronary syndromes than those with stable angina [16].…”

Reassessing the risk of hemodilutional anemia: Some new pieces to an old puzzle

“…[81][82][83] For example, eNOS expression is increased during exercise, 84 and its regulation may help to maintain microvascular health. 85 Recently, HIF-derived increases in skin iNOS expression have been shown to divert blood flow toward the skin, causing a reduction in kidney perfusion and accentuating renal hypoxic responses. 82 Finally, nNOS has been implicated in the regulation of a number of important cardiovascular responses: 1) In the brain, nNOS facilitates synaptic transmission and controls neuronal regulation of HR and mean arterial pressure; 86,87 nNOS can also regulate neurovascular control of cerebral blood flow; 88,89 2) In the heart, nNOS affects contraction and relaxation of cardiac myocytes by regulating intracellular calcium; 90 Fig.…”

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

“…The presence of iNOS mRNA and protein expression has been described in atherosclerotic human plaques in macrophages as well as endothelial and smooth muscle cells [106,162]. In support of a role for iNOS in promoting pathogenesis, iNOS expression was found in the majority of samples as early as the fatty streak stage and in all of the advanced stages of plaques coinciding with an increase in oxidized LDL and nitrated proteins [106].…”