Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase

Hinman A, Holst CR, Latham JC, Bruegger JJ, Ulas G, McCusker KP, Amagata A, Davis D, Hoff KG, Kahn-Kirby AH, Kim V, Kosaka Y, Lee E, Malone SA, Mei JJ, Richards SJ, Rivera V, Miller G, Trimmer JK, Shrader WD

PLoS One. 2018 Aug 15;13(8):e0201369. doi: 10.1371/journal.pone.0201369. eCollection 2018.

Abstract

Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme’s non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity.

Huwait EA

Folia Morphol (Warsz). 2018 Aug 14. doi: 10.5603/FM.a2018.0070. [Epub ahead of print]

Abstract

BACKGROUND:

L-carnitine and Vitamin E have antioxidant properties. This study aimed to assess the effectiveness of L-carnitine, Vitamin Eand the combination of them in protection against isoproterenol (ISO)-induced biochemical and histopathological changes in rat heart.

MATERIAL AND METHODS:

Fifty male Wistar rats assigned to 5 groups; control, ISO-treated group (100 mg/kg), ISO+vitamin E-treated group (100 IU/kg), ISO+L-carnitine (100 mg/kg) and ISO+vitamin E+L-carnitine treated group. At the end of the experiment, serum cardiac enzyme as well as the cardiac level Malondialdehyde (MDA), antioxidant enzymes and inflammatory cytokines IL-6, TNF-alpha were assessed. Histopathological changes in the left ventricle wall was assessed using the light and electron microscopy.

RESULTS:

Treating rats with vitamin E and L-carnitine could alleviate ISO-induced changes as it significantly reduced the serum level cardiac enzymes, MDA and IL-6, TNF-alpha and improved the antioxidants enzymes (SOD, GSPxase and GSRase). Histopathological, they improved cardiac fibers atrophy, hemorrhages between cardiac fibers, lost striations, and disturbed sarcomere structure. The combined effect of vitamin E and L-carnitine was more superior compared to the other groups.

CONCLUSION:

Combined administration of vitamin E, L-carnitine ameliorated the biochemical and histopathological cardiac affection induced by ISO. The effect seemed to be mediated through the antioxidant and anti-inflammatory effect of vitamin E, L-carnitine. Administration of these two element is recommended for patient at risk for myocardial infarction.

Kemnic TR, Coleman M

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2018-. 2018 Jul 24.

Excerpt

Vitamin E is all the following eight compounds alpha, beta, gamma, and delta-tocopherol and alpha, beta, gamma, and delta-tocotrienol. Alpha-tocopherol is the only compound of the eight that are known to meet human dietary needs. All of the vitamin E forms are absorbed in the small intestine, and then the liver metabolizes only alpha-tocopherol. The liver then removes and excretes the remaining vitamin E forms. Vitamin E deficiency is extremely rare in humans as it is unlikely caused by a diet consisting of low vitamin E. Rather, it tends to be caused by irregularities in dietary fat absorption or metabolism. Vitamin E is a lipid-soluble nutrient. Vitamin E may have a role in reducing atherosclerosis and lowering rates of ischemic heart disease. Premature infants have low vitamin E reserves due to vitamin E only able to cross the placenta in small amounts.

Wan Hasan WN, Chin KY, Jolly JJ, Abd Ghafar N, Soelaiman IN.

Endocr Metab Immune Disord Drug Targets. 2018 Apr 23. doi: 10.2174/1871530318666180423122409. [Epub ahead of print]

Abstract

BACKGROUND:

Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling.

OBJECTIVE:

This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential.

DISCUSSION:

Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans.

CONCLUSION:

mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

KEYWORDS:

bone; bone metabolism; mevalonate pathway; tocotrienol; vitamin E.

Lee H, Lim Y.

J Nutr Biochem. 2018 Mar 21;57:77-85. doi: 10.1016/j.jnutbio.2018.03.016. [Epub ahead of print]

Abstract

Chronic hyperglycemia induces impairment of muscle growth and development of diabetes mellitus (DM). Since skeletal muscle is the major site for disposal of ingested glucose, impaired glucose metabolism causes imbalance between protein synthesis and degradation which adversely affects physical mobility. In this study, we investigated the effect of tocotrienol-rich fraction (TRF) supplementation on skeletal muscle damage in diabetic mice. Diabetes was induced by a high-fat diet with streptozotocin (STZ) injection (100 mg/kg) in male C57BL/6J mice. After diabetes was induced (fasting blood glucose levels≥250 mg/dl), normal control (CON) and diabetic control (DMC) groups were administrated with olive oil, while TRF treatment groups were administrated with TRF (dissolved in olive oil) at low dose (100 mg/kg BW, LT) or high dose (300 mg/kg BW, HT) by oral gavage for 12 weeks. TRF supplementation ameliorated muscle atrophy, plasma insulin concentration and homeostatic model assessment estimated insulin resistance in diabetic mice. Moreover, TRF treatment up-regulated IRS-1 and Akt levels accompanied by increased translocation of GLUT4. Furthermore, TRF increased mitochondrial biogenesis by activating SIRT1, SIRT3 and AMPK in diabetic skeletal muscle. These changes were in part mechanistically explained by reduced levels of skeletal muscle proteins related to oxidative stress (4-hydroxynonenal, protein carbonyls, Nrf2 and HO-1), inflammation (NFkB, MCP-1, IL-6 and TNF-α), and apoptosis (Bax, Bcl₂ and caspase-3) in diabetic mice. Taken together, these results suggest that TRF might be useful as a beneficial nutraceutical to prevent skeletal muscle atrophy associated with diabetes by regulating insulin signaling via AMPK/SIRT1/PGC1α pathways in type 2 diabetic mice.

Su M, Wang D, Chang W, Liu L, Cui M, Xu T

Assay Drug Dev Technol. 2018 Feb 22. doi: 10.1089/adt.2017.831. [Epub ahead of print]

Abstract

Atherosclerosis is a major cause for cardiovascular diseases. High-density lipoprotein (HDL) may reduce atherosclerosis through several different mechanisms. HDL is composed of lipids, cholesterol, cholesteryl esters, triglycerides, and phospholipids, mainly phosphatidylcholine plus specialized proteins called apolipoproteins (apos). In this study, we prepared vitamin E containing HDL (V_E-HDL) that contains egg phosphatidylcholine, cholesterol, vitamin E, and two kinds of recombinant human apolipoproteins (rhapo)-rhapoA-I and rhapoE in vitro by the facilitation of cholate. After that, we studied the effects of V_E-HDL on foam cell formation, cellular cholesterol efflux, oxidative low-density lipoprotein (oxLDL)-stimulated oxidative stress, and apoptosis of macrophages to evaluate the protective efficacy of V_E-HDL on macrophages. As the results showed, we prepared a new type of reconstituent HDL with apolipoproteins and vitamin E for the first time. V_E-HDL has protective efficacy on macrophages. It has the prospect of becoming a therapeutic agent on atherosclerosis in the future.

Vineetha RC, Binu P, Arathi P, Nair RH

Toxicol Mech Methods. 2018 Jan 18:1-8. doi: 10.1080/15376516.2017.1422578. [Epub ahead of print]

Abstract

Arsenic trioxide (As₂O₃) is a potent drug for the treatment of acute promyelocytic leukemia (APL) and has achieved remarkable remissions in patients. Unfortunately, clinical reports have shown that the treatment is associated with cardiotoxicity. Many efforts have been made to mitigate drug-mediated cardiac damage using naturally occurring antioxidant compounds possessing free radical scavenging activity. The present investigation aims to explore protective role of L-ascorbic acid (L-AA) and α-tocopherol (α-TOC) from As₂O₃-induced oxidative stress in H9c2 cardiomyocytes through the evaluation of Nrf2 (nuclear factor erythroid 2-related factor 2) and Bcl-2 (B-cell lymphoma 2) transcription factors. The in vitro study was conducted using H9c2 cardiomyocytes. The evaluation of total antioxidant capacity, mitochondrial membrane potential, cellular calcium concentration and reactive oxygen species generation was performed. Oxidative stress (Nrf2) and anti-apoptotic (Bcl2) signaling indicators were measured by reverse transcriptase polymerase chain reaction. A depletion of the total antioxidant capacity and mitochondrial transmembrane potential were observed in As₂O₃-treated cardiomyocytes. In addition, the cellular calcium concentration and ROS generation were found to be increased on treatment with As₂O₃ with the alterations in the activity of transcription factors, Nrf2 and Bcl2. Co-treatment of antioxidant vitamins with As₂O₃ resulted in a significant reversal of oxidative stress and alteration on the antioxidant defense through the activation of Nrf2 and Bcl2. L-AA and α-TOC alleviates As₂O₃-induced oxidative stress in cardiac cells by activating Nrf2 and Bcl2 transcription factors that results in increased cell survival and prevents apoptosis.

Alshiek JA, Dayan L, Asleh R, Blum S, Levy AP, Jacob G

Diabetes Res Clin Pract. 2017 Sep;131:200-207. doi: 10.1016/j.diabres.2017.06.026. Epub 2017 Jul 13.

Abstract

Vascular dysfunction in both conduit arteries and small vessels is a major contributor to the development of cardiovascular disease (CVD) in diabetes mellitus (DM). In diabetes there is a process of systemic chronic inflammation accompanied by high oxidative stress causing a subsequent decrease in vascular reactivity and negatively affect the metabolic processes responsible for functioning of the microvasculature. Vitamin E is classified as an antioxidant due to its ability to scavenge lipid radicals and terminate oxidative chain reactions. We conducted a double-blinded cross-over study with vitamin E versus placebo in individuals with type 2DM and the Hp2-2 genotype and assessed different aspects of peripheral vascular function in these patients. Twenty patients completed the study with 10 individuals in each study cohort. We were able to show significant improvement of indirect indices of vascular function following 8weeks of treatment with vitamin E. This improvement was consistent for weeks even after stopping the vitamin E treatment. We concluded that a pharmacogenomic rationale utilizing the Hp genotype might potentially provide cardiovascular benefit with vitamin E.

Cheng HS, Ton SH, Tan JBL, Abdul Kadir K

Nutrients. 2017 Sep 7;9(9). pii: E984. doi: 10.3390/nu9090984.

Abstract

The clinical value of tocotrienols is increasingly appreciated because of the unique therapeutic effects that are not shared by tocopherols. However, their effect on metabolic syndrome is not well-established. This study aimed to investigate the effects of a tocotrienol-rich fraction (TRF) from palm oil in high-fat-diet-treated rats. Male, post-weaning Sprague Dawley rats were provided high-fat (60% kcal) diet for eight weeks followed by a TRF (60 mg/kg) treatment for another four weeks. Physical, metabolic, and histological changes were compared to those on control and high-fat diets respectively. High-fat feeding for eight weeks induced all hallmarks of metabolic syndrome. The TRF reversed systolic and diastolic hypertension, hypercholesterolemia, hepatic steatosis, impaired antioxidant defense, and myeloperoxidase hyperactivity triggered by the high-fat diet. It also conferred an inhibitory effect on protein glycation to reduce glycated hemoglobin A1c and advanced glycation end products (AGE). This was accompanied by the suppression of the receptor for advanced glycation end product (RAGE) expression in the liver. The treatment effects on visceral adiposity, glycemic control, triglyceride level, as well as peroxisome proliferator-activated receptor α and γ expression were negligible. To conclude, treatment with a TRF exhibited protective effects on the cardiovascular and liver health in addition to the amelioration of plasma redox imbalance and AGE-RAGE activation. Further investigation as a therapy for metabolic syndrome is therefore worthwhile.

Chen Y, Yin C, Yang Y, Fan Z, Shang J, Tan W.

J Electrocardiol. 2017 Jul - Aug;50(4):437-443. doi: 10.1016/j.jelectrocard.2017.03.007. Epub 2017 Mar 14.

Abstract

Ischemia/reperfusion (I/R) induces prolongation of QT interval and action potential duration (APD), which is a major cardiac electrical disorder in patients with arrhythmias. However, the mechanism of QT interval prolongation induced by I/R remains unclear. In the present study, we hypothesized that the rapid component of delayed rectifier potassium (I_Kr) channel plays an important role in I/R-induced QT interval prolongation. We observed a marked attenuation of I_Kr and a significant prolongation of action potential duration (APD) in a simulated I/R system with sodium dithionite (Na₂S₂O₄) in ventricular myocytes of guinea pigs. The I_Kr current density was inhibited by 64% and APD increased by 87% respectively. Moreover, the inhibition of I_Kr is primarily ascribed to overproduction of reactive oxygen species (ROS) by I/R, which can be partly reversed by antioxidant vitamin E (100μmol/L). The value of I_Kr tail current density increased from 0.516±0.040 pA/pF in I/R to 0.939±0.091 pA/pF when treated with vitamin E. Moreover, we also demonstrated that QTc interval was increased by I/R and reversed by Vitamin E in isolated guinea pig hearts. In conclusion, the inhibition of I_Kr is one of the underlying mechanisms of prolongation of QT interval and APD in I/R. Vitamin E might have a benefit in coronary reperfusion therapy.