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Improved Cardiovascular Function in Old Mice After N-Acetyl Cysteine and Glycine Supplemented Diet: Inflammation and Mitochondrial Factors.

ABSTRACT: Metabolic, inflammatory, and functional changes occur in cardiovascular aging which may stem from oxidative stress and be remediable with antioxidants. Glutathione, an intracellular antioxidant, declines with aging, and supplementation with glutathione precursors, N-acetyl cysteine (NAC) and glycine (Gly), increases tissue glutathione. Thirty-month old mice were fed diets supplemented with NAC or NAC+Gly and, after 7 weeks, cardiac function and molecular studies were performed. The NAC+Gly supplementation improved diastolic function, increasing peak early filling velocity, and reducing relaxation time, left atrial volume, and left ventricle end diastolic pressure. By contrast, cardiac function did not improve with NAC alone. Both diet supplementations decreased cardiac levels of inflammatory mediators; only NAC+Gly reduced leukocyte infiltration. Several mitochondrial genes reduced with aging were upregulated in hearts by NAC+Gly diet supplementation. These Krebs cycle and oxidative phosphorylation enzymes, suggesting improved mitochondrial function, and permeabilized cardiac fibers from NAC+Gly-fed mice produced ATP from carbohydrate and fatty acid sources, whereas fibers from control old mice were less able to utilize fatty acids. Our data indicate that NAC+Gly supplementation can improve diastolic function in the old mouse and may have potential to prevent important morbidities for older people.

SUBMITTER: Cieslik KA

PROVIDER: S-EPMC6093357 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Improved Cardiovascular Function in Old Mice After N-Acetyl Cysteine and Glycine Supplemented Diet: Inflammation and Mitochondrial Factors.

Cieslik Katarzyna A KA Sekhar Rajagopal V RV Granillo Alejandro A Reddy Anilkumar A Medrano Guillermo G Heredia Celia Pena CP Entman Mark L ML Hamilton Dale J DJ Li Shumin S Reineke Erin E Gupte Anisha A AA Zhang Aijun A Taffet George E GE

The journals of gerontology. Series A, Biological sciences and medical sciences 20180801 9

Metabolic, inflammatory, and functional changes occur in cardiovascular aging which may stem from oxidative stress and be remediable with antioxidants. Glutathione, an intracellular antioxidant, declines with aging, and supplementation with glutathione precursors, N-acetyl cysteine (NAC) and glycine (Gly), increases tissue glutathione. Thirty-month old mice were fed diets supplemented with NAC or NAC+Gly and, after 7 weeks, cardiac function and molecular studies were performed. The NAC+Gly suppl ...[more]

PMID: 29538624

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Project description:The discovery of the metallopeptide Ni(Cysteine-Glycine-Cysteine)(2-), Ni(CGC)(2-), in the A-cluster active site of Acetyl CoA Synthase has prompted the synthesis of many small molecule models which employ M(N(2)S(2)) complexes as metalloligands. In vitro studies have shown that nickel incorporates into the N(2)S(2) binding pocket even when copper is in the enzyme growth medium, while copper is preferentially taken up in the proximal site, displacing the catalytically active nickel. (Darnault, C.; Volbeda, A.; Kim, E.J.; Legrand, P.; Vernede, X.; Lindahl, P.A.; Fontecilla-Camps, J.C. Nat. Struct. Biol. 2003, 10, 271-279.) The work herein has been designed to address the chemical viability of copper(II) within the tripeptide N(2)S(2) ligand set. To this end, a series of CuN(2)S(2)(2-) complexes, the resin-bound, O-Cu(CGC)(2-) (A) and free Cu(CGC)(2-) (B) complexes, as well as Cu(ema)(2-) (C) and Cu(emi)(2-) (D) dianions, have been characterized by UV-vis, electron paramagnetic resonance (EPR), and electrospray ionization mass spectrometry (ESI-MS) spectroscopies, cyclic voltammetry (CV), and, where appropriate, X-ray diffraction studies, and compared to the Ni(II) congeners. EPR spectroscopic results have indicated that, in frozen N,N-dimethylformamide (DMF) solution, the copper complexes are distorted square planar structures with nitrogen and sulfur donors. This is consistent with X-ray diffraction measurements which also show copper(II) in a distorted square planar environment that is bereft of CuN(2)S(2)(2-) intermolecular interactions. Density-functional theory (DFT) calculations resulted in optimized structures that are consistent with crystallographic data and indicated highest occupied molecular orbital (HOMO)-singly occupied molecular orbital (SOMO) gaps of 5.01 and 4.68 eV for C and D, respectively. Optimized structures of Ni(ema)(2-) and Ni(emi)(2-) share the same basic characteristics as the copper(II) congeners. Electrochemical characterization of C and D resulted in a reversible Cu(III/II) couple at -1.20 V and - 1.40 V, respectively. Reactivity studies with Rh(CO)(2)(+) show similar donor capabilities for complexes A-D. Analysis of A shows that transmetalation does not occur. From competitive metal uptake studies on immobilized tripeptide it is concluded that the N(2)S(2)(4-) ligating unit has a slight preference for Cu(2+) over Ni(2+) and that the biosynthetic pathway responsible for constructing the distal site of ACS must be selective for nickel insertion or copper exclusion, or both.

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Dataset Information

Improved Cardiovascular Function in Old Mice After N-Acetyl Cysteine and Glycine Supplemented Diet: Inflammation and Mitochondrial Factors.

Publications

Improved Cardiovascular Function in Old Mice After N-Acetyl Cysteine and Glycine Supplemented Diet: Inflammation and Mitochondrial Factors.

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