Oxysterols

Under Construction

This page is currently under construction; possibly relevant findings are being gathered to be able to compose a coherent overview.

Oxidation

• In water, cholesterol oxidizes more rapidly. But at 125°C, autoxidation of cholesterol also occurs in the dry state.[1]
• Cholesterol incorporated in a membranes is relatively protected aginst oxidation.[2]
• Heating at 100°C for 8 hours, 5% of cholesterol was oxidized. The identified oxidation products (52% of total) were: 7-ketocholesterol (42%), 7β-hydroxycholesterol (20%), β-epoxycholesterol (16%), α-epoxycholesterol (12%), 7α-hydroxycholesterol (7%) and 25β-hydroxycholesterol (3%).[3]
• oxidized fatty acids in the diet contribute to serum lipoprotein oxidation.
• oxidized fatty acids in the diet accelerate atherosclerosis in cholesterol-fed rabbits.[4]
• Serum cholesterol is increased after consuming unoxidized cholesterol, similar to partially (5%) oxidized cholesterol, but only the oxidized cholesterol (25 mg/day) diet resulted in a 100% increase in fatty streak lesions in the aorta.[5]
• Elevated LDL levels represent one of the most important risk factors for atherosclerosis, cardiovascular morbidity and mortality. Both native and oxidized LDL are potent growth factors and regulate several other growth factors, for several cell types. Furthermore, the mitogenic effects of oxLDL may be mediated through lysophosphatidylcholine (LPC), lysophosphatidic acid (LPA), lactosylceramide (LacCer) sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC). [6]
• Cholesterol oxidation products are not equally distributed among plasma lipoproteins.[7][8]
• Elevated levels of oxidized LDL correlate with subclinical atherosclerosis and predict future cardiovascular events [9]Free Full Text [10]Free Full Text
• oxidized β-VLDL is degraded by macrophages at an accelerated rate compared with native β-VLDL.[11][12]
• oxidized β-VLDL leads to increased lipid accumulation in smooth muscle cells.[13][14]

Sphingomyelin & Calcification

• Aging is the single most important risk factor for cardiovascular diseases, and increased vessel rigidity appears to be a major hallmark of cardiovascular aging.[15]
• Sphingomyelin in arterial tissue (and relative to lecithin) increases with age.[16]
• Oxysterols promote atherosclerosis through sphingomyelin-mediated arterial calcification and thromboxane-mediated interruption of blood flow. [17]
• Oxidized LDL induces an immediate and oscillatory increase in intracellular calcium.[18]
• oxidized LDL-induced apoptosis of endothelial cells is calcium-dependent.[19]
• Oxidative modification of LDL results in the production of lipid peroxides and the conversion of phosphatidylcholine to lysophosphatidylcholine.[20]
• In bone tissue, locally synthesized (Smpd3 encoded-) sphingomyelinase stimulates bone calcification. Sphingomyelinase cleaves sphingomyelin to generate bioactive lipid metabolites (ceramide).[21]
• Lowering plasma sphingomyelin reduces atherosclerotic lesions. [22]
• Plasma sphingomyelin concentration is an independent predictor of coronary artery disease.[23] [
• Inhibiting sphingomyelin synthesis decreases atherosclerosis in mice.[24]
• the plasma from cardiac catheterized patients suffering from chest pains contained higher levels of oxysterols.[25]
• the plasma of patients with cardiovascular disease contains excess concentration of oxysterols, resulting in more calcium in endothelial cells.[26]
• Oxysterols (25- and 26-hydroxycholesterol) have an injurious effect on arterial cells. [27]
• Oxysterols (7 alpha OHC, 7 beta OHC, alpha epoxyC, beta epoxyC, 7ketoC, 26OHC, TriolC) replace cholesterol in the cell membrane, increasing calcium influx.[28]
• 27OHC decreases phosphatidylethanolamine and AA, and increases sphingomyelin, LA and calcium.[29]
• The arteries from patients who had had coronary artery bypass operations, contained elevated concentrations of oxysterols and sphingomyelin, increasing calcium influx into endothelial cells. The phospholipd sphingomyelin fraction in replaced arteries was 48.2%, compared to 24% in healthy arteries, and to 10% in arterial tissue from umbilical cords. [30]
• the newborn human placenta contained only about 10% sphingomyelin and 50% phosphatidylcholine.Full Free Text
• Depending on the oxidation rate and the ratio of oxysterols plus thiobarbituric acid reactive substances (TBARS) versus lysolecithin (obtained from phosphatidylcholine, inhibiting thromboxane synthesis), [31] oxidized LDL may stimulate thromboxane release by platelets [32], increasing blood clotting.

Sphingosine-1-phosphate (S1P)

• Sphingomyelin deposition and metabolism occurs in the atherosclerotic plaque, leading to the formation of sphingosine-1-phosphate (S1P). S1P receptor 2 (S1PR2) is expressed in bone marrow-derived macrophages and in macrophage-like foam cells in atherosclerotic plaques. S1PR2 retains macrophages in atherosclerotic plaques. S1PR2 signaling in the plaque macrophage regulates macrophage retention and inflammatory cytokine secretion, thereby promoting atherosclerosis. [33] Full Free Text
• Macrophages internalize oxidized LDL immune complexes (oxLDL-IC) and transform into activated foam cells. S1P may be generated extracellularly in response to oxidized LDL immune complexes.[34]
• oxLDL induces the immediate activation of sphingosine kinase (SK), which can increase sphingosine-1-phosphate (S1P) levels by phosphorylating sphingosine. Both S1P and oxLDL block macrophage apoptosis and producing calcium oscillations. [35] Full Free Text
• S1P is mainly released from activated platelets. release of S1P from activated platelets was increased by enhanced platelet sensitivity in hypercholesterolemia, which potentiated the ox-LDL-induced VSMC proliferation via EDG-1 receptor pathway.[36]
• Sphingosine-1-phosphate (SPP) is a major (and potent) Full Free Text polar sphingolipid metabolite (from ceramides, derived from sphingomyelin) released from activated platelets that (also) acts as an intracellular lipid messenger, regulating calcium mobilisation.[37]
• S1P is a mediator in inflammation and atherogenesis.[38]
• S1P acts via multiple signaling pathways. S1P induces vasoconstriction in vivo. S1P can act through both receptors and a novel intracellular pathway to activate store-operated calcium entry (SOCE) in vascular smooth muscle cells. Because S1P-induced SOCE contributes to vessel constriction and is increased in proliferative VSMCs, it is likely that S1P/SOCE signaling in proliferative VSMCs may play a role in vascular dysfunction such as atherosclerosis.[39] Full Free Text
• TNFalpha rapidly triggers S1P generation and activation of SPHK. Moreover, our data shows that SPHK1 is the isoform activated by TNFalpha, and plays an essential role on the TNFalpha-triggered intracellular Ca2+ signals.[40]
• The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances, particularly nitric oxide (NO), synthesized by nitric oxide synthase (eNOS). The release of NO is down-regulated by oxidative stress and oxidized LDL.[41] S1P inhibits IL-1beta induction of NO production and iNOS expression in rat vascular smooth muscle cells through multiple mechanisms, playing an important role in the ptrogression of atherosclerosis.[42]

• oxLDL induces neutral sphingomyelinase activity, evoking sphingomyelin turnover to ceramide.[43] Full Free Text oxLDL increased the activities of both acidic and alkaline ceramidases as well as sphingosine kinase, elevating S1P. [44] Full Free Text

Thromboxane

• Depending on the oxidation rate and the ratio of oxysterols plus thiobarbituric acid reactive substances (TBARS) versus lysolecithin (obtained from phosphatidylcholine, inhibiting thromboxane synthesis), [45] oxidized LDL may stimulate thromboxane release by platelets [46], increasing blood clotting.
• Trans fatty acids inhibit the synthesis of prostacyclin (a blood-clotting inhibitor) in the relative absence of AA.[47][48] Dietary Trans fatty acids did not alter prostacyclin levels.[49][50]
• Low concentrations of oxLDL inhibit thromboxane release by platelets and intracellular calcium.[51]
• Elevated oxLDL triggers platelet activation.[52]
• Aggregating platelets at sites of atherosclerotic injury release thromboxane A2(TXA2). Even low concentration of TXA2 released from aggregating platelets may potentiate the mitogenic effect of oxLDL at sites of vascular damage.[53]
• Selenoproteins in the vascular wall protect against oxysterol-induced vascular damage. When selenium (glutathione peroxidase) deficient, oxysterols elevate plasma thromboxane.[54]

Full Free Text

Abbreviations

• 7 alpha-hydroxycholesterol (7 alpha OHC)
• 7 beta-hydroxycholesterol (7 beta OHC)
• cholesterol 5 alpha,6 alpha-epoxide (alpha epoxyC)
• cholesterol 5 beta,6 beta-epoxide (beta epoxyC)
• 7-ketocholesterol (7ketoC)
• 25-beta-hydroxycholesterol (25 beta OHC)
• 25-hydroxycholesterol (25 OHC)
• 26-hydroxycholesterol (26 OHC)
• cholesterol-3 beta,5 alpha,6 beta-triol (TriolC)