Antioxidants to Prevent LDL Oxidation Act to Restore Macrophage Function and Reverse Atherosclerosis in Mice
Researchers here demonstrate that introducing an antioxidant into the diet, one that accumulates in cell lysosomes, helps to prevent macrophage dysfunction and thus reverse atherosclerotic plaque in an animal model of atherosclerosis. The hypothesis is that oxidized LDL particles, ingested and carried to lysosomes for degradation, are an important component of dysfunction in the macrophage cells responsible for clearing out lipid accumulations in blood vessel walls. Macrophages function well in youth, but are challenged and made dysfunctional in later life by the age-related increase in levels of oxidation of lipids and lipid carriers such as LDL particles. Strategies in clinical use to slow atherosclerosis have so far not directly targeted this challenge of oxidation and macrophage function, which may well be why they are of only limited benefit.
Multiple studies suggest that the presence of lysosomal cholesterol accumulation in macrophages, and not the total amount of intracellular lipids, is critical for the observed inflammatory response. We have shown that lysosomes in macrophages are a site of low-density lipoprotein (LDL) oxidation. Seven days after taking up mechanically aggregated LDL or sphingomyelinase aggregated LDL, mouse or human macrophage-like cells and human monocyte-derived macrophages generated ceroid in their lysosomes. Ceroid (lipofuscin) is a polymerized product of lipid oxidation found within foam cells in atherosclerotic lesions.
The lysosomal oxidation of LDL is catalyzed by oxidation-reduction active iron present in the lysosomes of macrophages through the generation of hydroperoxyl radicals at the lysosomal pH of 4.5. This oxidation is inhibited by cysteamine (2-aminoethanethiol), an antioxidant that accumulates in lysosomes. Cysteamine is used in patients for the lysosomal storage disease cystinosis, caused by the absence of the lysosomal cystine transporter cystinosin. Recently, we have shown that cysteamine reduces atherogenic conditions caused by lysosomal LDL oxidation, such as lysosomal dysfunction, cellular senescence, and secretion of various proinflammatory cytokines, such as interleukin-1β, TNF-α, and interleukin-6, and chemokines, such as CCL2, in human macrophages.
LDL receptor-deficient mice were fed a high-fat diet to induce atherosclerotic lesions. They were then reared on chow diet and drinking water containing cysteamine or plain drinking water. Aortic atherosclerosis was assessed, and samples of liver and skeletal muscle were analyzed. There was no regression of atherosclerosis in the control mice, but cysteamine caused regression of between 32% and 56% compared with the control group, depending on the site of the lesions. Cysteamine substantially increased markers of lesion stability, decreased ceroid, and greatly decreased oxidized phospholipids in the lesions. The liver lipid levels and expression of cluster of differentiation 68, acetyl-coenzyme A acetyltransferase 2, cytochromes P450 (CYP)27, and proinflammatory cytokines and chemokines were decreased by cysteamine. Skeletal muscle function and oxidative fibers were increased by cysteamine. There were no changes in the plasma total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, or triacylglycerol concentrations attributable to cysteamine.
In conclusion, inhibiting the lysosomal oxidation of LDL in atherosclerotic lesions by antioxidants targeted at lysosomes causes the regression of atherosclerosis and improves liver and muscle characteristics in mice and might be a promising novel therapy for atherosclerosis in patients.
In recent years there've been a couple of studies on lysosomal antioxidants and LDL oxidation in test tubes, a mouse here and there. IIRC the results were not so promising due to iron and to some extent copper causing LDL oxidation in spite of the antioxidant.
Is cysteamine really different from other antioxidants other than the price tag?
Time will tell if those problems can be overcome in low-density lipoprotein receptor-nondeficient humans. I wouldn't hold my breath.
When checking up on cysteamine it turns out it can help with skin discoloration
Medical uses
Cysteamine is used to treat cystinosis. It is available by mouth (capsule and extended release capsule) and in eye drops.[13][6][7][4][8][5][9][14]
When applied topically it can scavenge free radicals[15] and lighten skin that's been darkened as a result of post-inflammatory hyperpigmentation, sun exposure and Melasma.[16][17][18] There's tentative evidence suggesting that it may be a more effective depigmentation agent than hydroquinone, retinoids and topical corticosteroids in individuals suffering with chronic skin discoloration.[19][20][21] Topical application of cysteamine cream has also demonstrated similar efficacy to intradermal tranexamic acid injections for the treatment of Melasma but with much fewer adverse effects.[22]
However, it is a bit pricey
In 2013, the regular capsule of cysteamine cost about $8,000 per year; the extended release form that was introduced that year was priced at $250,000 per year.[24]
@cuberat
First thing I thought when I learned that cysteamine helps with skin discoloration was: 'Damn, does it remove lipofuscin?'
'Lipofuscin is the name given to fine yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion. It is considered to be one of the aging or "wear-and-tear" pigments, found in the liver, kidney, heart muscle, retina, adrenals, nerve cells, and ganglion cells.'
Haven't looked any further into it, though.
Cysteamine has a rather 'interesting' list of side effects, considering it is an antioxidant:
https://www.mayoclinic.org/drugs-supplements/cysteamine-oral-route/side-effects/drg-20068629
On the other hand, so does Vitamin A (Retinol)...
@me
It seems cysteamine 'removes' lipofuscin and according to Zhang et al. so does N-acetylcysteine.
.
The effects of lysosomotropic agents on normal and INCL cells provide further evidence for the lysosomal nature of palmitoyl-protein thioesterase function
Jui-Yun Lu, Linda A. Verkruyse, Sandra L. Hofmann
https://sci-hub.se/10.1016/S1388-1981(02)00158-0
.
'Zhang et al. [17] also noted
that the resolution of lipofuscin from cultured INCL cells
required continuous cysteamine treatment of the cells for 2
weeks, which is quite different from the rapid action of
cysteamine in cystinotic fibroblasts, and from the rapid
chemical reaction of cysteamine on cysteine thioesters that
was reported in vitro. Our results therefore cast doubt on
direct thioester cleavage as a mechanism for cysteamine
action in cells, as proposed, and suggest that the effects of
cysteamine may be more complex than previously understood.'
.
Lysosomal ceroid depletion by drugs: Therapeutic implications for a hereditaryn eurodegenerative disease of childhood
ZHONGJIAN ZHANG et al.
https://sci-hub.se/10.1038/86554
.
' We report here that two such drugs, phosphocysteamine and N-acetylcysteine, disrupt
thioester linkages in a model thioester compound, palmitoyl∼CoA. Most importantly, in lymphoblasts derived from INCL patients, phosphocysteamine, a known lysosomotrophic drug, mediates the depletion of lysosomal ceroids, prevents their re-accumulation and inhibits apoptosis. Our results define a novel pharmacological approach to lysosomal ceroid depletion...'
Instead of taking Cysteamine you can just take Pantethine (vit B5 analog) which breaks down into Cysteamine and Pantothenic Acid. It can be bought cheaply on amazon. Apparently it also results in twice the CoA as Pantothenic Acid.
@Kent what about a dosage of pantethine to have plasma concentration similar to cysteamine?
I wondered why they sell pantethine in 300mg pills. I've just found out:
Dr. Atkins' Vita-Nutrient Solution: Nature's Answer to Drugs "[...] In one published account [...] a daily 900 mg dose of pantethine led to a 32 percent drop in triglycerides, a 19 percent drop in total cholesterol, and a 21 percent drop in LDL. At the same time, [...] (HDL), rose by 23 percent. [...]".