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Can gas replace protein function? CO abrogates the oxidative toxicity of myoglobin.

Sher EA, Sholto AY, Shaklai M, Shaklai N - PLoS ONE (2014)

Bottom Line: The main cause of LDL oxidation by Hb was found to be hemin which readily transfers from Hb to LDL.These reactions were fully arrested by CO.The data are interpreted to suit several circumstances, some physiological, such as high muscle activity, and some pathological, such as rhabdomyolysis, ischemia/reperfusion and skeletal muscle disuse atrophy.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Outside their cellular environments, hemoglobin (Hb) and myoglobin (Mb) are known to wreak oxidative damage. Using haptoglobin (Hp) and hemopexin (Hx) the body defends itself against cell-free Hb, yet mechanisms of protection against oxidative harm from Mb are unclear. Mb may be implicated in oxidative damage both within the myocyte and in circulation following rhabdomyolysis. Data from the literature correlate rhabdomyolysis with the induction of Heme Oxygenase-1 (HO-1), suggesting that either the enzyme or its reaction products are involved in oxidative protection. We hypothesized that carbon monoxide (CO), a product, might attenuate Mb damage, especially since CO is a specific ligand for heme iron. Low density lipoprotein (LDL) was chosen as a substrate in circulation and myosin (My) as a myocyte component. Using oxidation targets, LDL and My, the study compared the antioxidant potential of CO in Mb-mediated oxidation with the antioxidant potential of Hp in Hb-mediated oxidation. The main cause of LDL oxidation by Hb was found to be hemin which readily transfers from Hb to LDL. Hp prevented heme transfer by sequestering hemin within the Hp-Hb complex. Hemin barely transferred from Mb to LDL, and oxidation appeared to stem from heme iron redox in the intact Mb. My underwent oxidative crosslinking by Mb both in air and under N2. These reactions were fully arrested by CO. The data are interpreted to suit several circumstances, some physiological, such as high muscle activity, and some pathological, such as rhabdomyolysis, ischemia/reperfusion and skeletal muscle disuse atrophy. It appear that CO from HO-1 attenuates damage by temporarily binding to deoxy-Mb, until free oxygen exchanges with CO to restore the equilibrium.

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Haptoglobin 2-2 inhibits dLDL oxidation.A solution containing dLDL (1.2 mg protein/ml) and ferric-Hb (12 µM) was incubated in presence or absence of Hp 2-2 (13 µM). LDL fractionation by charge following 3.5 hours of incubation was performed by fast anion exchange liquid chromatography. 1: dLDL alone (control); 2: dLDL+ferric Hb; 3: dLDL+ferric Hb+Hp; 4: Hp alone (control). A representative result of 4 independent experiments is shown.
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pone-0104075-g003: Haptoglobin 2-2 inhibits dLDL oxidation.A solution containing dLDL (1.2 mg protein/ml) and ferric-Hb (12 µM) was incubated in presence or absence of Hp 2-2 (13 µM). LDL fractionation by charge following 3.5 hours of incubation was performed by fast anion exchange liquid chromatography. 1: dLDL alone (control); 2: dLDL+ferric Hb; 3: dLDL+ferric Hb+Hp; 4: Hp alone (control). A representative result of 4 independent experiments is shown.

Mentions: As seen from Fig. 3, the elution peaks of Hp alone (peak 4) and LDL alone (peak 1) appear at ∼50 minutes, while the elution peak of oxidized LDL (peak 2) was at ∼60 minutes. This may be due to an increase in negative charge on LDL, caused by its oxidation. In contrast, the presence of Hp in the reaction mixture caused the elution peak to remain at LDL's original position (peak 3).


Can gas replace protein function? CO abrogates the oxidative toxicity of myoglobin.

Sher EA, Sholto AY, Shaklai M, Shaklai N - PLoS ONE (2014)

Haptoglobin 2-2 inhibits dLDL oxidation.A solution containing dLDL (1.2 mg protein/ml) and ferric-Hb (12 µM) was incubated in presence or absence of Hp 2-2 (13 µM). LDL fractionation by charge following 3.5 hours of incubation was performed by fast anion exchange liquid chromatography. 1: dLDL alone (control); 2: dLDL+ferric Hb; 3: dLDL+ferric Hb+Hp; 4: Hp alone (control). A representative result of 4 independent experiments is shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128816&req=5

pone-0104075-g003: Haptoglobin 2-2 inhibits dLDL oxidation.A solution containing dLDL (1.2 mg protein/ml) and ferric-Hb (12 µM) was incubated in presence or absence of Hp 2-2 (13 µM). LDL fractionation by charge following 3.5 hours of incubation was performed by fast anion exchange liquid chromatography. 1: dLDL alone (control); 2: dLDL+ferric Hb; 3: dLDL+ferric Hb+Hp; 4: Hp alone (control). A representative result of 4 independent experiments is shown.
Mentions: As seen from Fig. 3, the elution peaks of Hp alone (peak 4) and LDL alone (peak 1) appear at ∼50 minutes, while the elution peak of oxidized LDL (peak 2) was at ∼60 minutes. This may be due to an increase in negative charge on LDL, caused by its oxidation. In contrast, the presence of Hp in the reaction mixture caused the elution peak to remain at LDL's original position (peak 3).

Bottom Line: The main cause of LDL oxidation by Hb was found to be hemin which readily transfers from Hb to LDL.These reactions were fully arrested by CO.The data are interpreted to suit several circumstances, some physiological, such as high muscle activity, and some pathological, such as rhabdomyolysis, ischemia/reperfusion and skeletal muscle disuse atrophy.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Outside their cellular environments, hemoglobin (Hb) and myoglobin (Mb) are known to wreak oxidative damage. Using haptoglobin (Hp) and hemopexin (Hx) the body defends itself against cell-free Hb, yet mechanisms of protection against oxidative harm from Mb are unclear. Mb may be implicated in oxidative damage both within the myocyte and in circulation following rhabdomyolysis. Data from the literature correlate rhabdomyolysis with the induction of Heme Oxygenase-1 (HO-1), suggesting that either the enzyme or its reaction products are involved in oxidative protection. We hypothesized that carbon monoxide (CO), a product, might attenuate Mb damage, especially since CO is a specific ligand for heme iron. Low density lipoprotein (LDL) was chosen as a substrate in circulation and myosin (My) as a myocyte component. Using oxidation targets, LDL and My, the study compared the antioxidant potential of CO in Mb-mediated oxidation with the antioxidant potential of Hp in Hb-mediated oxidation. The main cause of LDL oxidation by Hb was found to be hemin which readily transfers from Hb to LDL. Hp prevented heme transfer by sequestering hemin within the Hp-Hb complex. Hemin barely transferred from Mb to LDL, and oxidation appeared to stem from heme iron redox in the intact Mb. My underwent oxidative crosslinking by Mb both in air and under N2. These reactions were fully arrested by CO. The data are interpreted to suit several circumstances, some physiological, such as high muscle activity, and some pathological, such as rhabdomyolysis, ischemia/reperfusion and skeletal muscle disuse atrophy. It appear that CO from HO-1 attenuates damage by temporarily binding to deoxy-Mb, until free oxygen exchanges with CO to restore the equilibrium.

Show MeSH
Related in: MedlinePlus