Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure

Iida, Shinichiro; Chu, Yi; Weiß, Robert M.; Yu, Kaijiang; Faraci, Frank M.; Heistad, Donald D.

doi:10.1152/ajpheart.00080.2006

Cited by 27 publications

(23 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In WT mice, endothelial dysfunction was relatively modest following the induction of HF. This was a rather surprising finding, since previous studies have reported that humans, rats, and mice with HF have substantial endothelial dysfunction (2,3,22,23,34). Interestingly, we did observe a significant increase in endothelial NOS in WT mice with HF.…”

Section: Discussionsupporting

confidence: 58%

“…Although our group has demonstrated that antioxidants or viral overexpression of SOD improve vascular function in HF (22,23) and other disease states (6,16,37), these studies did not examine the role of endogenous antioxidant defense mechanisms in protecting against endothelial dysfunction. Thus coordinated increases in antioxidant enzymes in WT mice may play an important role in protecting against endothelial dysfunction in HF.…”

Section: Discussionmentioning

confidence: 99%

“…All relative light unit (RLU) counts were normalized to the surface area of the aortic ring. This method has been described previously in detail (23).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure

Miller¹,

Peotta²,

Chu³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

Brooks RM, Heistad DD. MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure. Am J Physiol Heart Circ Physiol 298: H1600 -H1607, 2010. First published March 19, 2010; doi:10.1152/ajpheart.01108.2009.-Endothelial function is impaired by oxidative stress in chronic heart failure (HF). Mechanisms that protect against increases in oxidative stress in HF are not clear. The goal of this study was to determine whether manganese superoxide dismutase (MnSOD) plays a key role in protecting against endothelial dysfunction in HF. Endothelial function and gene expression were examined in aorta from wild-type mice (MnSOD ϩ/ϩ ) and mice deficient in MnSOD (MnSOD ϩ/Ϫ ) 12 wk after ligation of the left coronary artery (LCA). LCA ligation produced similar size myocardial infarctions in MnSOD ϩ/ϩ and MnSOD ϩ/Ϫ mice and reduced ejection fraction to ϳ20% in both groups. Maximal relaxation in response to acetylcholine was 78 Ϯ 3% (mean Ϯ SE) and 66 Ϯ 8% in sham-operated MnSOD ϩ/ϩ and MnSOD ϩ/Ϫ mice, respectively. Expression of antioxidant enzymes increased in MnSOD ϩ/ϩ mice with HF, and maximal relaxation to acetylcholine was slightly impaired (68 Ϯ 4%). Greater endothelial dysfunction was observed in MnSOD ϩ/Ϫ mice with HF (46 Ϯ 5%, P Ͻ 0.05), which was significantly improved by polyethylene glycol-catalase but not Tempol. Incubation with the nonspecific cyclooxygenase (COX) inhibitor indomethacin or the COX1 inhibitor valeryl salicylate, but not the COX-2 inhibitor NS-398, significantly improved relaxation to acetylcholine in HF mice (maximum relaxation ϭ 74 Ϯ 5, 91 Ϯ 1, and 58 Ϯ 5%). These data suggest that MnSOD plays a key role in protecting against endothelial dysfunction in HF. A novel mechanism was identified whereby chronic increases in oxidative stress, produced by mitochondrial SOD deficiency, impair vascular function via a hydrogen peroxide-dependent, COX1-dependent, endothelium-derived contracting factor. mitochondria; oxidative stress; vasomotor function; endothelium; endothelium-derived contracting factor; cyclooxygenase ENDOTHELIAL DYSFUNCTION IS associated with increases in oxidative stress and appears to play a significant role in the pathophysiology of several diseases (5). Humans and experimental animals develop endothelial dysfunction and increases in oxidative stress after the induction of chronic heart failure (HF; see Refs. 2,17,21,24,30,32,35,42,43). Additionally, several of the most effective treatments for HF (especially inhibitors of the renin-angiotensin system) are associated with improvements in endothelial function, reductions in NAD(P)H oxidase activity, and reductions in oxidative stress (19,34,38).Superoxide dismutases (SOD) provide important protection against oxidative stress in blood vessels (14). Expression of copper-zinc SOD (CuZnSOD) and manganese SOD (MnSOD) appears to be relatively well preserved in a variety of tissue beds in humans with HF, but several groups have shown that expression of extracellular SOD (ecSOD) is significantly reduced (35). Although rec...

show abstract

Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure

Miller¹,

Peotta²,

Chu³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…They demonstrated that when these 3 exogenous EC-SOD forms were incubated with cells, only the wild-type form entered mouse endothelial cells via endocytosis, 121 indicating that an intact heparin-binding domain is necessary for internalization. The heparin-binding domain variant was also shown to provide little protection from oxidative stress in humans, 122 and elevated plasma levels of this variant were associated with increased risk of ischemic heart disease, compared with the 142 ng/ml of plasma EC-SOD in non-carriers. 123 It is well established that EC-SOD is a major extracellular antioxidant.…”

Section: Extracellular Antioxidant Enzymes Extracellular Superoxide Dmentioning

confidence: 99%

Redox Regulation in the Extracellular Environment

Ottaviano

Handy

Loscalzo

2008

Circ J

125

100

View full text Add to dashboard Cite

Molecular oxygen is involved in the oxidation of substrates used to produce energy; however, normal metabolism can also generate harmful (bio)chemical byproducts. These deleterious products are partially reduced forms of oxygen, and include free radicals such as superoxide anion radical, hydroxyl radical, or highly oxidizing non-radical species such as hydrogen peroxide (H2O2) and lipid peroxides, which are collectively known as ROS. 1 ROS typically derive from normal metabolism, activated leukocytes, and ambient oxygen in the environment. The production and accumulation of ROS and their downstream effects can be controlled or attenuated by antioxidants. When the ability of antioxidants to eliminate harmful cellular and extracellular ROS is compromised, the balance between ROS generation and antioxidant function to eliminate ROS is shifted in favor of an accumulation of oxidants, which defines the state of oxidative stress in a cell or organism. Oxidative damage can affect DNA, lipids, and proteins, and eventually compromise cell integrity. Many studies have implicated ROS in the pathological processes leading to heart disease, cancer, aging, AIDS, and inflammatory and autoimmune diseases.Oxidants, especially free radicals, are highly reactive. Superoxide can react within milliseconds with nitric oxide (NO) to produce peroxynitrite (ONOO -), a reactive nitrogen species (RNS). The nitrosium cation and nitroxyl anion are other RNS derived from NO. 2 Peroxynitrite is a strong oxidant involved in the nitrosative modification of proteins and lipids. Owing to its rapid reaction with NO, superoxide may modulate NO bioavailability and, subsequently, regulate vascular function. 3 Circulation Journal Vol.72, January 2008The cytosol, mitochondria, peroxisomes, and plasma are all potential sites of ROS formation. 4 The major sources of ROS are enzymatic via nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), xanthine oxidase, myeloperoxidase, endothelial NO synthase (eNOS), or as a consequence of normal mitochondrial respiration. In vascular cells, other enzymatic sources of ROS include cytochrome P450 isoenzymes, lipoxygenase, cyclooxygenase, heme oxygenase, and glucose oxidase. 1,3,[5][6][7] Most reviews to date have focused on the role of intracellular antioxidants that eliminate ROS from the intracellular environment. There are, however, several extracellular antioxidants that also play an equally important role in limiting ROS accumulation in the extracellular environment. Along with limiting ROS accumulation, extracellular redox status is essential for maintaining protein stability and function.The major enzymes important for the elimination of extracellular H2O2 are glutathione peroxidase-3 (GPx-3) and peroxiredoxin IV (Prx IV). Other extracellular antioxidants involved in ROS elimination include paraoxonase (PON), thioredoxin (Trx), Trx reductase (TrxR), glutaredoxin (Grx), extracellular superoxide dismutase (EC-SOD), and extracellular glutathione (GSH).Some of these antioxidants, notably glutathione...

show abstract

“…-associated oxidative stress by enhancing ecSOD has been applied successfully in various experimental disease models [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] (Table I). For example, ecSOD has been shown to restore erectile function in streptozotocin-induced diabetes, 33 protect against vascular dysfunction with aging, 19 blunt ischemia/reperfusion-induced liver injury, 32 reduce systemic vascular resistance and arterial pressure in spontaneously hypertensive rats, 21 improve endothelial dysfunction in hypertension and in heart failure models, 23,35 and ameliorate inflammatory arthritis.…”

Section: Decreasingmentioning

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

View full text Add to dashboard Cite

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...

show abstract

Vascular effects of a common gene variant of extracellular superoxide dismutase in heart failure

Cited by 27 publications

References 32 publications

MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure

MnSOD protects against COX1-mediated endothelial dysfunction in chronic heart failure

Redox Regulation in the Extracellular Environment

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

Contact Info

Product

Resources

About