Asymmetric Dimethylarginine Increases Mononuclear Cell Adhesiveness in Hypercholesterolemic Humans

Abstract

Abstract-Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is elevated in hypercholesterolemia. This study was designed to determine the role of ADMA in the increased mononuclear cell adhesiveness observed in human hypercholesterolemia. In patient studies, plasma ADMA levels were determined by high-performance liquid chromatography. Functional mononuclear leukocyte adhesion assays were performed in parallel, and flow cytometry was used to characterize bound monocytes and T lymphocytes. Hypercholesterolemic patients were then placed on an oral L-arginine regimen of 14 or 21 g/d and studied over 12 weeks. In cell culture studies, bovine aortic endothelial cells were incubated with varied concentrations of ADMA. Monocytoid cells were cocultured with these bovine aortic endothelial cells, and their adhesiveness was assessed by use of a binding assay. Flow cytometry was used to quantify adhesion molecule expression. Plasma ADMA levels and adhesiveness of mononuclear cells (specifically, monocytes and T lymphocytes) were elevated in hypercholesterolemic patients. Adhesiveness was inversely correlated with the plasma L-arginine/ADMA ratio. Oral administration of L-arginine normalized plasma L-arginine/ADMA ratios and attenuated monocyte and T-lymphocyte adhesiveness. ADMA had no direct effect on the adhesiveness of mononuclear cells. However, monocytes became hyperadhesive when cocultured with ADMA-exposed endothelial cells. In human hypercholesterolemia, the plasma L-arginine/ADMA ratio is inversely correlated with mononuclear cell adhesiveness. Restoration of the L-arginine/ADMA ratio to control levels normalizes mononuclear cell adhesiveness. Our studies suggest that the elaboration of endothelium-derived nitric oxide affects the behavior of circulating T lymphocytes and monocytes. Key Words: L-arginine Ⅲ atherosclerosis Ⅲ monocytes Ⅲ endothelium Ⅲ T lymphocytes M onocytes and T lymphocytes are the predominant inflammatory cells found in atherosclerotic plaques. Indeed, the adhesion of mononuclear cells to the endothelium is a key initial event in atherogenesis that precedes the formation of fatty streaks. [1][2][3] In hypercholesterolemic (HC) humans, peripheral blood mononuclear cells exhibit increased adhesiveness for endothelial cells in ex vivo adhesion assays. 4,5 Differences in monocyte surface markers have been detected by flow cytometry between HC and normocholesterolemic (NC) humans, although the functional significance is unclear. 6 Molecular signaling mechanisms for the altered behavior of mononuclear cells are likely multifactorial and may involve inflammatory cytokines, 7 LDL, 8,9 platelet-activating factor, 10 circulating soluble adhesion molecules, 11 and reduced bioactivity of endotheliumderived nitric oxide (NO).NO has been shown to modulate the behavior of circulating blood elements. In vivo, NO inhibits leukocyte adherence in the early stages of hypercholesterolemia in the rat. 12 Furthermore, endothelium-derived NO is able to increase cGMP and reduce the abili...

Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

“…Plasma arginine levels are unlikely to be rate-limiting for protein synthesis in our groups of subjects, as they did not differ, and oral arginine supplementation, despite increasing plasma arginine levels, did not increase plasma ADMA or SDMA [42]. However, a significant contributor to the MA differences found by us is likely to be DDAH activity [4,9,34,43,44].…”

Effects of L-thyroxine treatment on early markers of atherosclerotic disease in children with subclinical hypothyroidism

“…NO is an anti-atherosclerotic molecule involved in a wide variety of regulatory mechanisms of the CV system, including vascular tone and structure and platelet and monocyte adhesion (31,34). Small modifications in ADMA concentrations may affect endothelial NO production, vascular tone, and systemic vascular resistance (35), and increased ADMA levels have been associated with endothelial dysfunction and increased IMT in adults (31).…”

Pathogenic Cycle Between the Endogenous Nitric Oxide Synthase Inhibitor Asymmetrical Dimethylarginine and the Leukocyte-Derived Hemoprotein Myeloperoxidase

“…Accordingly, elevated ADMA concentrations are associated with increased leukocyte activation. 6,7 The major pathway for elimination of ADMA is its metabolism by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which exists in 2 isoforms (DDAH1 and DDAH2), yielding L-citrulline and dimethylamine. 8,9 A minor portion of circulating ADMA is excreted via the kidneys.…”