Homocysteine induces oxidative-nitrative stress in heart of rats: prevention by folic acid.
ABSTRACT Hyperhomocysteinemia is a risk factor for cardiovascular disease, stroke, and thrombosis; however, the mechanisms by which homocysteine triggers these dysfunctions are not fully understood. In the present study, we investigated the effect of chronic hyperhomocysteinemia on some parameters of oxidative stress, namely thiobarbituric acid reactive substances, an index of lipid peroxidation, 2',7'-dichlorofluorescein (H(2)DCF) oxidation, activities of antioxidant enzymes named superoxide dismutase and catalase, as well as nitrite levels in heart of young rats. We also evaluated the effect of folic acid on biochemical alterations elicited by hyperhomocysteinemia. Wistar rats received daily subcutaneous injection of homocysteine (0.3-0.6 μmol/g body weight) and/or folic acid (0.011 μmol/g body weight) from their 6th to the 28th day of life. Controls and treated rats were killed 1 h and/or 12 h after the last injection. Results showed that chronic homocysteine administration increases lipid peroxidation and reactive species production and decreases enzymatic antioxidant defenses and nitrite levels in the heart of young rats killed 1 h, but not 12 h after the last injection of homocysteine. Folic acid concurrent administration prevented homocysteine effects probable by its antioxidant properties. Our data indicate that oxidative stress is elicited by chronic hyperhomocystenemia, a mechanism that may contribute, at least in part, to the cardiovascular alterations characteristic of hyperhomocysteinemic patients. If confirmed in human beings, our results could propose that the supplementation of folic acid can be used as an adjuvant therapy in cardiovascular alterations caused by homocysteine.
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ABSTRACT: Hyperhomocysteinemia (hHCy) is recognized as a co-morbid risk factor of human stroke. It also aggravates the ischemia-induced injury by increased production of reactive oxygen species, and by the homocysteinylation and thiolation of functional proteins. Ischemic preconditioning represents adaptation of the CNS to sub-lethal ischemia, resulting in increased brain tolerance to subsequent ischemia. We present here an overview of recent data on the homocysteine (Hcy) metabolism and on the genetic and metabolic causes of hHCy-related neuropathologies in humans. In this context, the review documents for an increased oxidative stress and for the functional modifications of enzymes involved in the redox balance in experimentally induced hHCy. Hcy metabolism leads also to the redox imbalance and increased oxidative stress resulting in elevated lipoperoxidation and protein oxidation, the products known to be included in the neuronal degeneration. Additionally, we examine the effect of the experimental hHCy in combination with ischemic insult, and/or with the preischemic challenge on the extent of neuronal degeneration as well as the intracellular signaling and the regulation of DNA methylation. The review also highlights that identification of the effects of co-morbid factors in the mechanisms of ischemic tolerance mechanisms would lead to improved therapeutics, especially the brain tissue.Cellular and Molecular Neurobiology 09/2014; 35(1). DOI:10.1007/s10571-014-0112-3 · 2.20 Impact Factor
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ABSTRACT: Our earlier studies have highlighted that an altered one carbon metabolism (vitamin B12, folic acid, and docosahexaenoic acid) is associated with preeclampsia. Preeclampsia is also known to be associated with oxidative stress and inflammation. The current study examines whether maternal folic acid, vitamin B12 and omega-3 fatty acid supplementation given either individually or in combination can ameliorate the oxidative stress markers in a rat model of pregnancy induced hypertension (PIH). Pregnant Wistar rats were assigned to control and five treatment groups: PIH; PIH + vitamin B12; PIH + folic acid; PIH + Omega-3 fatty acids and PIH + combined micronutrient supplementation (vitamin B12 + folic acid + omega-3 fatty acids). L-Nitroarginine methylester (L-NAME; 50 mg/kg body weight/day) was used to induce hypertension during pregnancy. Blood Pressure (BP) was recorded during pregnancy and dams were dissected at d20 of gestation. Animals from the PIH group demonstrated higher (p<0.01 for both) systolic and diastolic BP; lower (p<0.01) pup weight; higher dam plasma homocysteine (p<0.05) and dam and offspring malondialdehyde (MDA) (p<0.01), lower (p<0.05) placental and offspring liver DHA and higher (p<0.01) tumor necrosis factor-alpha (TNF-ά) levels as compared to control. Individual micronutrient supplementation did not offer much benefit. In contrast, combined supplementation lowered systolic BP, homocysteine, MDA and placental TNF-ά levels in dams and liver MDA and protein carbonyl in the offspring as compared to PIH group. Key constituents of one carbon cycle (folic acid, vitamin B12 and DHA) may play a role in reducing oxidative stress and inflammation in preeclampsia.PLoS ONE 11/2014; 9(11):e111902. DOI:10.1371/journal.pone.0111902 · 3.53 Impact Factor
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ABSTRACT: In light of the limited data concerning the role of N-methyl-D-aspartate (NMDA) receptors in cardiac function, the aim of the present study was to determine the role of NMDA receptors in cardiac function, as well as the possible role played by the oxidative stress induced by the overstimulation of NMDA receptors in isolated rat heart. The hearts of male, Wistar albino rats (n = 24, 12 in each experimental group, BM 180-200 g) were retrogradely perfused at a constant perfusion pressure (70 cm H2O), using the Langendorff technique, and cardiodynamic parameters were determined during the subsequent administration of DL-homocysteine thiolactone (DL-Hcy TLHC) alone, the combination of DL-Hcy TLHC and dizocilpine (MK-801), and MK-801 alone. In the second experimental group, the order of the administration of each of the substances was reversed. The oxidative stress biomarkers, including thiobarbituric acid reactive substances (TBARS), NO2 (-), O2 (-) and H2O2, were each determined spectrophotometrically. DL-Hcy TLHC and MK-801 depressed cardiac function. DL-Hcy TLHC decreased oxidative stress, a finding that contrasted with the results of the experiments in which MK-801 was administered first. The findings of this study were suggestive of the likely role played by NMDA receptors in the regulation of cardiac function and coronary circulation in isolated rat heart.Molecular and Cellular Biochemistry 12/2014; 401(1-2). DOI:10.1007/s11010-014-2296-8 · 2.39 Impact Factor