Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes

Tamai, M; Furuta, Hiroto; Kawashima, Hiromichi; Doi, Asako; Hamanishi, Tohru; Shimomura, Hiroko; Sakagashira, Setsuya; Nishi, Masahiro; Sasaki, Hideyuki; Sanke, Tokio; Nanjo, Kishio

doi:10.1016/j.diabres.2005.05.006

Cited by 51 publications

(49 citation statements)

References 19 publications

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“…Table II summarizes newly identified variants in the human ecSOD gene. 123,124 The functional significance of these variants, however, remains unknown. 125 …”

Section: Ecsod Gene Variantsmentioning

confidence: 99%

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Qin

Reszka

Fukai

et al. 2008

Translational Research

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Extracellular superoxide dismutase (ecSOD) is the major extracellular scavenger of superoxide () and a main regulator of nitric oxide (NO) bioactivity in the blood vessel wall, heart, lungs, kidney, and placenta. Involvement of has been implicated in many pathological processes, and removal of extracellular by ecSOD gene transfer has emerged as a promising experimental technique to treat vascular disorders associated with increased oxidant stress. In addition, recent studies have clarified mechanisms that regulate ecSOD expression, tissue binding, and activity, and they have provided new insight into how ecSOD interacts with other factors that regulate vascular function. Finally, studies of a common gene variant in humans associated with disruption of ecSOD tissue binding suggest that displacement of the enzyme from the blood vessel wall may contribute to vascular diseases. The purpose of this review is to summarize recent research findings related to ecSOD function and gene transfer and to stimulate other investigations into the role of this unique antioxidant enzyme in vascular pathophysiology and therapeutics.Oxidative stress induced by superoxide anion ( ) produced in vascular cells is involved in the pathogenesis of cardiovascular and metabolic diseases, including atherosclerosis, 1 ischemia-reperfusion injury, 2 diabetes, 3 hyperlipidemia, 4 and hypertension. 5 Moreover, may also contribute to pulmonary hypertension, 5 erectile dysfunction, 6 cerebral vasospasm, 7 and other disorders associated with vascular dysfunction. Consequently, strategies to reduce levels of have emerged as promising approaches to treating cardiovascular diseases and other conditions associated with enhanced oxidative stress. In mammalian tissues, 3 isoforms of SODs exist: Cu/Zn SOD (SOD1), Mn SOD (SOD2), and extracellular SOD (ecSOD or SOD3). SOD1 is an abundant copper-and zinc-containing cellular protein that is present in the cytosol, nucleus, peroxisomes, and mitochondrial inner membrane. Its primary function is to lower the intracellular steady-state concentration of . SOD1 mutations are associated with neural diseases such as amyotrophic lateral sclerosis. 8 SOD2 is a mitochondrial enzyme that disposes of generated by respiratory chain activity. SOD2 can be induced to protect against prooxidant insults. Conversely, SOD2 activity is decreased in physiologic aging and in diseases such as progeria, cancer, asthma, and transplant rejection. 9 ecSOD, another copper-and zinc-containing dismutase, is a primary antioxidant enzyme secreted to the extracellular space. ecSOD is expressed highly in selected tissues, including blood vessels, heart, lungs, kidney, placenta, and extracellular fluids. ecSOD plays an important role in regulating blood pressure and vascular contraction, at least in part, through modulating the endothelial function by controlling the levels of extracellular and nitric oxide bioactivity in the vasculature. 10,11 ecSOD has also been proposed to play an important role in neurologic, pulmonary, and arthriti...

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“…Table II summarizes newly identified variants in the human ecSOD gene. 123,124 The functional significance of these variants, however, remains unknown. 125 …”

Section: Ecsod Gene Variantsmentioning

confidence: 99%

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Qin

Reszka

Fukai

et al. 2008

Translational Research

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“…Polymorphisms in the ecSOD gene have been linked to several diseases in humans, including type 2 diabetes, acute lung injury, ischemic heart disease, chronic obstructive pulmonary disease, and preeclampsia (52)(53)(54)(55)(56). However, the impact of ecSOD on the susceptibility of the human population to pathogenic infections has not been studied.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver

et al. 2016

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Listeria monocytogenes is a Gram-positive intracellular pathogen that causes spontaneous abortion in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals. Although L. monocytogenes can usually be effectively treated with antibiotics, there is still around a 25% mortality rate with individuals who develop clinical listeriosis. Neutrophils are innate immune cells required for the clearance of pathogenic organisms, including L. monocytogenes. The diverse roles of neutrophils during both infectious and noninfectious inflammation have recently gained much attention. However, the impact of reactive oxygen species, and the enzymes that control their production, on neutrophil recruitment and function is not well understood. Using congenic mice with varying levels of extracellular superoxide dismutase (ecSOD) activity, we have recently shown that the presence of ecSOD decreases clearance of L. monocytogenes while increasing the recruitment of neutrophils that are not protective in the liver. The data presented here show that ecSOD activity does not lead to a cell-intrinsic increase in neutrophil-homing potential or a decrease in protection against L. monocytogenes. Instead, ecSOD activity enhances the production of neutrophil-attracting factors and protects hyaluronic acid (HA) from damage. Furthermore, neutrophils from the livers of ecSOD-expressing mice have decreased intracellular and surface-bound myeloperoxidase, are less capable of killing phagocytosed L. monocytogenes, and have decreased oxidative burst. Collectively, our data reveal that ecSOD activity modulates neutrophil recruitment and function in a cell-extrinsic fashion, highlighting the importance of the enzyme in protecting tissues from oxidative damage. Listeria monocytogenes is a Gram-positive bacterium that can be found in the soil, fruits, vegetables, meats, and dairy products. Ingestion of L. monocytogenes-contaminated foods can cause spontaneous abortions in pregnant women, as well as septicemia, meningitis, and gastroenteritis, primarily in immunocompromised individuals (1). Surprisingly, clinical listeriosis results in an ϳ25% mortality rate despite the use of antibiotics (1), which makes understanding the immune response against the pathogen important. Furthermore, L. monocytogenes is a widely used model pathogen to study and understand host-pathogen interactions due to its ease of use and manipulation.Neutrophils are short-lived immune cells that differentiate in the bone marrow from the common myeloid progenitor (2). Under normal homeostatic conditions, most neutrophils are retained in the bone marrow until inflammation leads to signaling for their egress. One of the mechanisms by which neutrophils are recruited out of the bone marrow and into tissues is through the increased production of CXCL1 and CXCL2 (3, 4), which are both induced by the interleukin 23 (IL-23)/IL-17 pathway (5, 6). During lipopolysaccharide (LPS)-induced hepatic injury, hyaluronic acid (HA)-CD44 interactions faci...

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“…On the other hand, HE functions as an indirect radical scavenger and induces the release of EC-SOD from endothelial cells in vivo [10]- [13]. EC-SOD is one kind of SOD [22] [23], containing Cu 2+ [24], and we do not have to be concerned about immunogenicity since it is an endogenous enzyme [25]. Accordingly, we have focused on its beneficial effect as a radical scavenger.…”

Section: Discussionmentioning

confidence: 99%

Middle Molecular Weight Heparinyl Amino Acid Derivatives (MHADs) Function as Indirect Radical Scavengers <i>in Vitro</i>

Takeda¹,

Toda²,

Nakamura³

2016

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We conducted the novel synthesis of middle molecular weight heparinyl amino acid derivatives (MHADs) to reduce the adverse effect of heparin (HE) based on its anticoagulant activity. Subsequently, we investigated the radical scavenging effects of 12 kinds of MHAD on cultured human umbilical vein endothelial cells (HUV-ECs) damaged by oxygen free radicals using xanthine and xanthine oxidase in vitro. As a result, middle molecular weight heparinyl phenylalanine, middle molecular weight heparinyl leucine, and middle molecular weight heparinyl tyrosine showed significant protective effects on HUV-ECs. In conclusion, these three HE derivatives might be candidates for therapeutic agents to treat diseases attributed to peroxidation.

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Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes

Cited by 51 publications

References 19 publications

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver

Middle Molecular Weight Heparinyl Amino Acid Derivatives (MHADs) Function as Indirect Radical Scavengers <i>in Vitro</i>

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Extracellular superoxide dismutase gene polymorphism is associated with insulin resistance and the susceptibility to type 2 diabetes

Cited by 51 publications

References 19 publications

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Extracellular superoxide dismutase (ecSOD) in vascular biology: an update on exogenous gene transfer and endogenous regulators of ecSOD

Extracellular Superoxide Dismutase Enhances Recruitment of Immature Neutrophils to the Liver

Middle Molecular Weight Heparinyl Amino Acid Derivatives (MHADs) Function as Indirect Radical Scavengers &lt;i&gt;in Vitro&lt;/i&gt;

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Middle Molecular Weight Heparinyl Amino Acid Derivatives (MHADs) Function as Indirect Radical Scavengers <i>in Vitro</i>