The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 16 No. 9 • October 2013

Extracellular Superoxide Dismutase (EC-SOD) Protects Against Atherosclerosis and Supports Hippocampal Neurogenesis

EC-SOD May Be Induced by Natural Hypo­methylation Agents Such as Curcumin and EGCG

Extracellular superoxide dismutase (EC-SOD) is part of the superoxide defense system present in the vascular wall that plays an important role in normal redox homeostasis by regulating superoxide activity there, for example, by reducing atherogenic superoxide oxidation of low density lipoprotein (LDL). A new paper1 now reports that EC-SOD can be induced by 5-azacytidine, a DNA methyltransferase inhibitor commonly used in experimental research. Curcumin (along with other curcuminoids, major active components of turmeric root) and EGCG have also been identified as DNA methyltransferase inhibitors (hypomethylation agents)1A,1B and, hence, might also be able to induce EC-SOD activity.

EC-SOD has become the subject of increasing numbers of research publications as a result of its important anti-inflammatory action against superoxide in the vascular system. In fact, EC-SOD acts as an important anti-inflammatory and anti-oxidative stress agent in monocytes and macrophages that are observed to accumulate in atherosclerotic plaques and to act as promoters of atherosclerosis.1

A large literature is evolving to explain the regulation of genetic expression via epigenetics, a modification of histone proteins associated with DNA that alters the histones without changing the chemical structure of the DNA itself. The researchers1 here observed changes in DNA methylation in the promoter and coding regions of EC-SOD that “suggest the strong possibility that DNA methylation within promoter and coding regions might regulate cell-specific expression of EC-SOD in human monocytic cells.”1

Another epigenetic modification, histone acetylation, is also involved in gene regulation. Here the researchers studied the effects of histone acetylation/deacetylation, mediated by histone acetyltransferase (HAT) and/or histone deacetylase (HDAC) on EC-SOD expression. They found that TPA (12-0-tetra-decanoylphorbol-13-acetate) treatment significantly decreased the expression of EC-SOD in U937 cells but increased it in THP-1 cells, determining the effect of histone modification, especially H3 and H4 acetylation, in TPA-inducible EC-SOD expression in THP-1 cells.

The most interesting findings here were the ones related to increased EC-SOD expression by decreasing methylation of its promoter and coding regions because of the possibility of using easily available and safe natural products curcumin (found in turmeric root with related curcuminoids) and EGCG as hypomethylating agents. As the authors explain, “the presence of a high level of EC-SOD throughout the vessel walls can contribute to the regulation of nitric oxide-derived vasodilation by preventing the formation of peroxynitrite.” Moreover, they say, “it has been shown that EC-SOD protects arteries from ischemia-induced cytotoxicity and reduces infarct sizes.” Note that hydrogen selectively destroys peroxynitrite.

EC-SOD Promotes Long-Term Survival of Newborn Neurons

A paper from last year2 reported that EC-SOD was important in a mouse model of neurogenesis by comparing mice in which EC-SOD was either knocked out, was normal in wild type (WT) mice, or was overexpressed in other mice. EC-SOD was important in progenitor cell proliferation, dendritic development, and long-term survival of newborn neurons. The study also “suggested that maintenance of the dendritic system following cranial irradiation was important for preservation of neurocognitive functions.”2

In a 2013 review paper,3 researchers noted that “… increasing SOD3 [EC-SOD] levels in various experimental disease models, e.g., chemically induced diabetes, hypertension, and inflammatory arthritis, reduced oxidative stress and improved disease state, thereby placing SOD3 as a central therapeutic target.”

1. Kamiya et al. Epigenetic regulation of extracellular-superoxide dismutase in human monocytes. Free Radic Biol Med. 61:197-205 (2013).
1A. Liu et al. Curcumin is a potent DNA hypomethylation agent. Bioorg Med Chem Lett. 19:706-9 (2009).
1B. Fang et al. Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 63:7563-70 (2003).
2. Zou et al. Extracellular superoxide dismutase is important for hippocampal neurogenesis and preservation of cognitive functions after irradiation. Proc Natl Acad Sci USA. 109(52):21522-7 (2012).
3. Frank et al. Targeting the redox balance in inflammatory skin conditions. Int J Molec Sci. 14:9126-67 (2013).

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