Low levels of plasma soluble receptor for advanced glycation end products are associated with severe leukoaraiosis in acute stroke patients
Introduction
Advanced glycation end products (AGEs), the products of non-enzymatic glycation and oxidation of proteins and lipids, are known to accumulate in circulating blood and in vessel walls, especially in diabetic patients, but in non-diabetic patients as well [1], [2], [3], [4]. The receptor for AGEs (RAGE), a multiligand member of the immunoglobulin superfamily of cell surface molecules [5], [6], is implicated in the pathogenesis of human diabetic vascular disease through ligand-triggered RAGE-dependent cellular activation, including stimulation of RAGE expression, production of proinflammatory cytokines, and induction of oxidative stress [7], [8], [9]. A secreted isoform of RAGE, termed soluble RAGE (sRAGE), can neutralize the adverse effects of RAGE signaling by acting as a decoy [10], [11]. Reduced levels of circulating sRAGE were observed in non-diabetic men with coronary artery disease [12], suggesting that the AGEs-RAGE system contributed to the development of not only diabetic microangiopathy, but also macroangiopathy, regardless of diabetic state.
The etiology of stroke involves macroangiopathy as well as microangiopathy predominantly due to hypertension. Few studies have addressed the pivotal roles of the AGEs-RAGE system in acute stroke patients. The aim of this study is to examine plasma sRAGE levels associated with various clinical features, including stroke subtype, stroke severity, grade of leukoaraiosis, and other cardiovascular risk factors, in acute stroke patients.
Section snippets
Patient selection
The single-center, hospital-based prospective study was approved by the Institutional Research and Ethics Committee of the National Cardiovascular Center, Osaka, Japan. Five hundred, seventy-six patients were admitted within three days of stroke onset to our Stroke Care Unit from February 2005 to August 2007. Not counted in this group were patients with subarachnoid hemorrhage due to a ruptured aneurysm and those with massive brain hemorrhage requiring neurosurgical treatment. Of the 576
Results
Median values of plasma sRAGE concentration in each stroke subtype were as follows; 1010 pg/ml (250–2700 pg/ml) in ABI, 933 pg/ml (331–3110 pg/ml) in LI, 1280 pg/ml (271–4720 pg/ml) in CEI, 1050 pg/ml (266–3300 pg/ml) in OI, and 943 pg/ml (190–2990 pg/ml) in PICH (Fig. 1). Distributions of plasma sRAGE concentrations were significantly different among the five stroke subtypes (p = 0.001).
Frequencies of smoking, AF, eGFR, PICH, and levels of HDL cholesterol were significantly different among the quartiles
Discussion
We showed that low levels of plasma sRAGE were associated with a high grade of DWMH, and with a high NIHSS score on admission in acute stroke patients. The contribution of AGEs-RAGE signaling pathways to pathogenesis should be different between acute and chronic disorders. The administration of sRAGE reduced functional recovery and regeneration in mice with acutely injured peripheral nerves [19], and Rong et al. suggested that RAGE signaling in inflammatory cells and peripheral neurons plays an
Acknowledgments
This study was supported in part by a grant from the Mitsubishi Pharma Research Foundation, by a grant from the Takeda Medical Research Foundation, by Research Grants for Cardiovascular Diseases (20C-1, 19C-3, 21A-4) from the Ministry of Health, Labor and Welfare of Japan and by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science.
References (33)
- et al.
Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface
J Biol Chem
(1992) - et al.
Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins
J Biol Chem
(1992) - et al.
Receptor for advanced glycation endproducts: a multiligand receptor magnifying cell stress in diverse pathologic settings
Adv Drug Deliv Rev
(2002) - et al.
cDNA cloning of a novel secreted isoform of the human receptor for advanced glycation end products and characterization of cells co-expressing cell-surface scavenger receptors and Swedish mutant amyloid precursor protein
Brain Res Mol Brain Res
(1999) - et al.
Albuminuria, but not metabolic syndrome, is a significant predictor of stroke recurrence in ischemic stroke
J Neurol Sci
(2009) - et al.
On behalf of the collaboraters for developing Japanese equation for estimating GFR. Revised equations for estimated GFR from serum creatinine in Japan
Am J Kidney Dis
(2009) - et al.
The receptor for advanced glycation end products is induced by the glycation products themselves and tumor necrosis factor-alpha through nuclear factor-kappa B, and by 17beta-estradiol through SP-1 in human vascular endothelial cells
J Biol Chem
(2000) - et al.
Soluble receptor for advanced glycation end products in patients with decreased renal function
Am J Kidney Dis
(2006) - et al.
Advanced glycation end-products and the progress of diabetic vascular complications
Physiol Res
(2004) - et al.
Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes
Cardiovasc Res
(2004)