The formation of free radicals by cardiac myocytes under oxidative stress and the effects of electron-donating drugs

Abstract

The interaction of myoglobin with H2O2 leads via a two-electron oxidation process to the formation of ferryl myoglobin. Metmyoglobin is more readily activated than oxymyoglobin to the ferryl states, which are capable of inducing peroxidative damage to membranes. E.p.r. and optical spectroscopic studies show that the thiol-containing compounds N-(2-mercaptopropionyl) glycine and N-acetylcysteine and the trihydroxamate desferrioxamine attenuate these processes by reducing the ferryl myoglobin species to metmyoglobin, with the formation of thiyl radicals and the desferrioxamine nitroxide radical respectively. Biochemical investigations of the potential for myoglobin in ruptured myocytes to be involved in radical generation, when under oxidative stress, and of the nature of the resulting species, were also undertaken. E.p.r. spectroscopic studies revealed the formation of a radical species which is capable of inducing membrane lipid peroxidation. The interaction of the thiol compounds and desferrioxamine with components of myocardial tissue under these conditions results in the generation of thiol-derived radical species and the desferrioxamine nitroxide radical respectively. These data, along with those obtained using optical spectrocopy, support the assignment of the identity of the radical species generated from the myocytes as the ferryl myoglobin radical.

A Causative Role for Redox Cycling of Myoglobin and Its Inhibition by Alkalinization in the Pathogenesis and Treatment of Rhabdomyolysis-induced Renal Failure

“…Importantly, unlike the Haber-Weiss/Fenton reactions involving free iron, this reaction is not dependent on the generation of superoxide or hydrogen peroxide; it can be driven solely by endogenous lipid hydroperoxides (17)(18)(19)(20). This hypothesis may also explain the partial efficacy of desferrioxamine to protect against renal failure in the rat model of rhabdomyolysis, since desferrioxamine is capable of reducing ferryl-Mb and its associated globin radical to the ferric form (21,22). Interestingly, nitric oxide also partially protects against the renal failure (23).…”

Oxidative modulation of marcaine and lekoptin in H9C2 rat myoblasts

“…Cardiomyocytes have been reported to express two NOS isoforms , endothelial and inducible, in disease states [8][9][10] . It was also reported that cardiac cells express neither iNOS nor eNOS immunoreactivity in both infracted and normal myocardium [11][12][13].…”

Reaction of Human Myoglobin and H2O2

“…Importantly, we reiterate that hydroxyl radicals do not appear to be involved in the transfer of oxidative damage to the protein (22,23) at least under the experimental conditions employed here. In any case, the risk of hydroxyl radical formation in the current study has been prevented by the use of the iron chelator DTPA throughout.…”

“…Additionally, globin ⅐ may undergo subsequent chemistry (20) and is capable of oxidizing other biological molecules (21). Importantly, hydroxyl radicals do not appear to be involved in the transfer of oxidative damage to either protein or target molecules (22,23).…”