Abstract
Carotid artery stenosis (CS) is a well-established risk factor for stroke. Increased proinflammatory chemokines, enhanced metallothionein (MT), and altered metal homeostasis may play roles in atherosclerosis progression and plaque destabilization. MT may sequester zinc during chronic inflammation, provoke zinc deficiency, and modulate NK cell cytotoxicity. A recent investigation of older patients with diabetes and atherosclerosis showed an association between the -209 A/G MT2A polymorphism, CS, and zinc status. In this study, we evaluated the relationship between two MT2A polymorphisms (-209 and + 838 locus), metal status, and inflammatory/immune response in older patients with CS only (the CS1 group) or with CS and previous cerebrovascular episodes (transient ischemic attack or stroke) (the CS2 group). A total of 506 individuals (188 CS1, 100 CS2, and 218 healthy controls) were studied. Atherosclerotic patients (CS1 and CS2) showed increased levels of MT, MCP-1, and RANTES, reduced NK cell cytotoxicity, and altered trace element concentrations (zinc, copper, magnesium, iron). The +838 C/G MT2A polymorphism was differently distributed in CS1 and CS2 patients, who displayed the GG genotype (C-) with significantly higher frequency than elderly controls. C- carriers showed increased MCP-1 and decreased NK cell cytotoxicity, CD56+ cells, and intracellular zinc availability along with decreased zinc, copper, and magnesium content in erythrocytes and increased iron in plasma. C- carriers also showed a major incidence of soft carotid plaques. In conclusion, the +838 C/G MT2A polymorphism seems to influence inflammatory markers, zinc availability, NK cell cytotoxicity, and trace element status, all of which may promote CS development.
Highlights
Carotid artery stenosis (CS) is a known risk factor for cerebrovascular events associated with oxidative stress and alterations in metal metabolism [1,2]
We found levels of copper and magnesium to be reduced in plasma (P < 0.05; P < 0.01) but not decrease in red blood cell (RBC), while iron levels were increased in RBC (P < 0.05) but not in plasma
A significant increment of C- carrier frequencies was observed in CS1 and CS2 patients compared with elderly controls (OR = 1.525; P = .042, 95% CI = 1.019–2.282 and odds ratios (OR) = 2.13, P = .004, 95% CI = 1.27–3.56, respectively) as determined by Fisher exact test using the approximation of Woolf
Summary
Carotid artery stenosis (CS) is a known risk factor for cerebrovascular events associated with oxidative stress and alterations in metal metabolism [1,2]. Zinc deficiency impairs the integrity of the endothelial cells [4] while favoring lipid peroxidation by enhancing oxidative-stress [5] and may play a critical role in atherogenesis [6]. Other trace elements, such as magnesium and copper, are involved in the pathogenesis of atherosclerosis [7,8] and have both been found to be reduced in atherosclerotic patients [9,10]. Increased iron (Fe) stores are associated with enhanced atherosclerosis risk [12]
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