Aluminum induces lipid peroxidation and aggregation of human blood platelets

Abstract

Aluminum (Al 3+ ) intoxication is thought to play a major role in the development of Alzheimer's disease and in certain pathologic manifestations arising from long-term hemodialysis. Although the metal does not present redox capacity, it can stimulate tissue lipid peroxidation in animal models. Furthermore, in vitro studies have revealed that the fluoroaluminate complex induces diacylglycerol formation, 43-kDa protein phosphorylation and aggregation. Based on these observations, we postulated that Al 3+ -induced blood platelet aggregation was mediated by lipid peroxidation. Using chemiluminescence (CL) of luminol as an index of total lipid peroxidation capacity, we established a correlation between lipid peroxidation capacity and platelet aggregation. Al 3+ (20-100 µM) stimulated CL production by human blood platelets as well as their aggregation. Incubation of the platelets with the antioxidants nor-dihydroguaiaretic acid (NDGA) (100 µM) and n-propyl gallate (NPG) (100 µM), inhibitors of the lipoxygenase pathway, completely prevented CL and platelet aggregation. Acetyl salicylic acid (ASA) (100 µM), an inhibitor of the cyclooxygenase pathway, was a weaker inhibitor of both events. These findings suggest that Al 3+ stimulates lipid peroxidation and the lipoxygenase pathway in human blood platelets thereby causing their aggregation.

Determination of serum aluminum, platelet aggregation and lipid peroxidation in hemodialyzed patients

“…The hemodialysis patients exhibited significantly higher aluminum levels than the controls. However, we found no correlation between high aluminum content and peroxidation or platelet aggregation (Table 3), as reported in other studies (13,30). It is noteworthy that the increased plasma peroxidation events do not reflect the production of MDA exclusively from platelets, but also from other cell elements such as erythrocytes (6) and leukocytes (7).…”

“…It has been reported in the literature that chronic renal failure patients undergoing prolonged hemodialysis show increased levels of aluminum in their sera (24)(25)(26)(27). Although this metal does not display redox capacity, it is capable of inducing peroxidation in cerebral tissue (8) and platelet aggregation in vitro (13). In addition, a high level of this metal is also associated with pathologies such as Alzheimers encephalopathy, amyotrophic lateral sclerosis and ageing (28,29).…”

“…Furthermore, aluminum in combination with fluoride, forming the fluoraluminate complex (11), activates phospholipase A 2 and ß-thromboglobulin release in human blood platelets (12). We have observed that aluminum induces lipid peroxidation and aggregation of human blood platelets (13). All of these events probably constitute the basis for the abnormalities found in chronic renal failure.…”

Evidence supporting a biological role for aluminum in chromatin compaction and epigenetics

“…Interestingly, there appears to be a strong evolutionary pressure for specific amino acid residues to be selected for incorporation into peptides and proteins that reduces their potential for self-aggregation, and precipitation, from aqueous solutions [7]. Despite such evolutionary selection, aluminum efficiently aggregates several different classes of organic molecules in solution, such as amyloid peptides [8], non-amyloid components [9], cell cyto-structural neurofilaments [10], milk casein phospho-proteins [11], blood coagulation glycoproteins [12] and small, irregularlyshaped anuclear cells also known as thromobocytes (blood platelets) [13]. Further, aluminum has also been shown to associate with aggregated amyloid plaque cores, which may be in a relatively nonspecific fashion, but have immunopathological and pro-inflammatory consequences in neurodegenerative brain disease [8,9,[14][15][16].…”

“…For example, there are high-field 19.6 T 27 Al solid-state MAS NMR and modeling data suggesting that specific 3 dimensional geometries of nucleic acids and peptides bearing electron-rich side groups may indeed direct aluminum binding, to function in a highly efficient coordination, cross-linking and permanent silencing of specific gene regions [2,20]. Lastly, there is ample evidence that the ectopic association of aluminum with genes, proteins and lipids appears to contribute to various pathologies, especially in diseases associated with unscheduled biomolecular aggregation [8][9][10][11][12][13][14][15][18][19][20][21][22][23]. The highly unusual reactivity of biosphere-abundant aluminum toward genetic signaling is further described and illustrated in the figures and legends.…”