Cysteamine inhibits lysosomal oxidation of low density lipoprotein in human macrophages and reduces atherosclerosis in mice

Abstract

Background and aimsWe have shown previously that low density lipoprotein (LDL) aggregated by vortexing is internalised by macrophages and oxidised by iron in lysosomes to form the advanced lipid/protein oxidation product ceroid. We have now used sphingomyelinase-aggregated LDL, a more pathophysiological form of aggregated LDL, to study lysosomal oxidation of LDL and its inhibition by antioxidants, including cysteamine (2-aminoethanethiol), which concentrates in lysosomes by several orders of magnitude. We have also investigated the effect of cysteamine on atherosclerosis in mice.MethodsLDL was incubated with sphingomyelinase, which increased its average particle diameter from 26 to 170 nm, and was then incubated for up to 7 days with human monocyte-derived macrophages. LDL receptor-deficient mice were fed a Western diet (19–22 per group) and some given cysteamine in their drinking water at a dose equivalent to that used in cystinosis patients. The extent of atherosclerosis in the aortic root and the rest of the aorta was measured.ResultsConfocal microscopy revealed lipid accumulation in lysosomes in the cultured macrophages. Large amounts of ceroid were produced, which colocalised with the lysosomal marker LAMP2. The antioxidants cysteamine, butylated hydroxytoluene, amifostine and its active metabolite WR-1065, inhibited the production of ceroid. Cysteamine at concentrations well below those expected to be present in lysosomes inhibited the oxidation of LDL by iron ions at lysosomal pH (pH 4.5) for prolonged periods. Finally, we showed that the extent of atherosclerotic lesions in the aortic root and arch of mice was significantly reduced by cysteamine.ConclusionsThese results support our hypothesis that lysosomal oxidation of LDL is important in atherosclerosis and hence antioxidant drugs that concentrate in lysosomes might provide a novel therapy for this disease.

Association Between Low-Density Lipoprotein Cholesterol and Platelet Distribution Width in Acute Ischemic Stroke

“…Therefore, in our study, we selected LDL-C as the main research object to investigate the interaction between LDL-C and PDW. Oxidized LDL-C and platelet adhesion play an important role in endothelium-mediated vasodilation and hemodynamic changes in the peripheral circulation ( 14 , 15 ). In 2007, Hsiai and colleagues showed that apolipoprotein B-100 nitration is involved in hemodynamic changes, modulating the focal nature of atherogenesis ( 16 ).…”

Effect of vitamin E on low density lipoprotein oxidation at lysosomal pH

“…It has been argued that multiple antioxidants might be required for a disease in which multiple oxidants might be involved or that the trials were conducted with older patients in whom oxidative stress had become progressively less important with age [35,36]. The studies of a-tocopherol and LDL oxidation in vitro were carried out at pH 7.4, however, whereas it is possible that LDL oxidation in atherosclerotic lesions occurs in the lysosomes of macrophages at a pH of about 4.5 catalysed by iron [21,25]. We show here that in marked contrast to the expected inhibition by a-tocopherol of LDL oxidation by Cu 2þ at pH 7.4, a-tocopherol does not inhibit LDL oxidation by Cu 2þ or Fe 3þ at pH 4.5, although it inhibits LDL oxidation by higher concentrations of Fe 2þ at pH 4.5.…”

“…the large clinical trials of a-tocopherol were ineffective. It would be desirable to conduct clinical trials of antioxidants that accumulate in lysosomes and inhibit the oxidation of LDL at acidic pH, such as cysteamine [22][23][24][25].…”

“…We have shown previously that LDL can be oxidised by iron in the lysosomes of macrophages [21] and that this causes the secretion of inflammatory cytokines [22]. The antioxidant cysteamine, which accumulates in lysosomes, inhibits the lysosomal oxidation of LDL [22][23][24][25] and decreases atherosclerosis in LDL receptor-deficient mice [25]. The oxidation of LDL by ferrous ion at lysosomal pH (pH 4.5) was not effectively inhibited by a-tocopherol [26].…”

Transcriptome profiling of in vitro-matured oocytes from a korean native cow (hanwoo) after cysteamine supplementation

“…Cysteamine inhibits LDL oxidative reactions facilitated by free radicals and ameliorates lysosomal stresses and protects from proteolysis. 38 The oxidized LDL is associated with NF-kB activation. 39 Besides, LOX-1 may be involved in cyclic AMP (cAMP) signaling pathway regulation in oocyte maturation.…”