Gene Transfer of Extracellular Superoxide Dismutase Reduces Arterial Pressure in Spontaneously Hypertensive Rats

Chu, Yi; Iida, Shinichiro; Lund, Donald D.; Weiß, Robert M.; DiBona, Gerald F.; Watanabe, Yoshimasa; Faraci, Frank M.; Heistad, Donald D.

doi:10.1161/01.res.0000057755.02845.f9

Cited by 149 publications

(136 citation statements)

References 59 publications

(63 reference statements)

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“…Results of gene transfer in the present study suggest that in vivo administration of ECSOD with fully active binding capacity may afford protection against vascular dysfunction produced by endotoxin. Based on effects of gene transfer of ECSOD in previous studies (9,12) of hypertension in rats and subarachnoid hemorrhage in rabbits and our present studies, we think it is likely that administration of exogenous SOD, that can bind to blood vessels, may prove to be beneficial in settings other than acute inflammation, such as atherosclerosis and diabetes, in which vascular superoxide is elevated.…”

Section: Discussionmentioning

confidence: 58%

“…In a previous study (9) using gene transfer in vivo in rats, ECSOD activity was elevated in plasma after either AdECSOD or AdECSOD-HBD. Based on immunohistochemistry studies, however, ECSOD protein was found bound to endothelium and vascular muscle only after gene transfer of AdECSOD but not AdECSOD-HBD (9). Thus the HBD is critical for localization of ECSOD to the vascular wall.…”

Section: Discussionmentioning

confidence: 86%

“…The importance of binding ECSOD to vascular tissue for antioxidant protection of vasomotor function during inflammation is not clear. In recent studies, we suggested that the HBD is necessary for antihypertensive effects of ECSOD (9) and protection against vasospasm after subarachnoid hemorrhage (28). To our knowledge, the present study is the first to examine effects of ECSOD or the role of its HBD on vasomotor function after LPS.…”

mentioning

confidence: 68%

“…Dr. Chu modified the cDNA from human ECSOD to make the recombinant virus (9); and 3) AdCMV LacZ containing the reporter gene for ␤-galactosidase was used as a control virus (8). Adenovirus was propagated at the Vector Core Laboratory of the University of Iowa and stored at Ϫ80°C until used.…”

Section: Adenoviral Vectormentioning

confidence: 99%

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Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Lund¹

2004

American Journal of Physiology-Heart and Circulatory Physiology

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transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin. Am J Physiol Heart Circ Physiol 287: H805-H811, 2004; 10.1152/ajpheart.00907.2003 impairs vascular function, in part by generation of reactive oxygen species. One goal of this study was to determine whether gene transfer of extracellular SOD (ECSOD) improves vascular responsiveness in LPS-treated rats. A second goal was to determine whether effects of ECSOD are dependent on the heparin-binding domain of the enzyme, which facilitates binding of ECSOD to the outside of cells. Adenoviruses containing ECSOD (AdECSOD), ECSOD with deletion of its heparin-binding domain (AdECSOD-HBD), or a control virus (AdLacZ) were injected intravenously into rats. Three days later, vehicle or LPS (10 mg/kg ip) was injected. After 24 h, vascular reactivity was examined in aortic rings in vitro. Maximum relaxation to acetylcholine was 95 Ϯ 1% (means Ϯ SE) after AdlacZ plus vehicle and 77 Ϯ 3% after AdlacZ plus LPS (P Ͻ 0.05). Responses to calcium ionophore A-23187 and submaximal concentrations of nitroprusside also were impaired by LPS. Gene transfer of ECSOD, but not AdECSOD-HBD, improved (P Ͻ 0.05) relaxation to acetylcholine and A-23187 after LPS. Maximum relaxation to acetylcholine was 88 Ϯ 3% after LPS plus AdECSOD. Superoxide was increased in aorta after LPS, and the levels were reduced after AdECSOD but not AdECSOD-HBD. LPS-induced adhesion of leukocytes to aortic endothelium was reduced by AdECSOD but not by AdECSOD-HBD. We conclude that after gene transfer in vivo, binding of ECSOD to arteries effectively decreases the numbers of adherent leukocytes and levels of superoxide and improves impaired endothelium-dependent relaxation produced by LPS. acetylcholine; adenovirus; rats; hydroethidine LPS PRODUCES IMPAIRMENT OF endothelium-dependent vascular relaxation (3,4,15). Several studies suggest that endothelial dysfunction in LPS-treated vessels may be produced, in part, by increased levels of reactive oxygen species (ROS), especially superoxide, in blood vessels (15,21). SOD, which reduces superoxide to hydrogen peroxide, improves endothelium-dependent relaxation in several pathological conditions in which superoxide is elevated in blood vessels (6, 10, 11, 18 -20, 28).Extracellular SOD (ECSOD), in contrast to other isoforms of SOD, is a secreted protein found predominantly outside of cells (12). A COOH-terminal binding domain has affinity for heparin [thus heparin-binding domain (HBD)] or sulfated proteoglycans, which facilitate binding of ECSOD to the external surfaces of many cells, including endothelial cells (12). Truncated forms of ECSOD, without HBDs or with decreased heparin-binding affinity, normally constitute a small percentage of endogenous ECSOD (12) and may, or may not, be important for vascular function. Decreases in ECSOD with high affinity for heparin, and increases in forms of ECSOD with low affinity for heparin, have been observed in atherosclerosis (12). Thus decreased function of the HBD on ECSOD may...

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 68%

Section: Adenoviral Vectormentioning

confidence: 99%

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Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Lund¹

2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…Increased content of superoxide radical (O 2 ¯) was noted in the arteries of spontaneously hypertensive rats; in this case genetic transfer of EC-SOD ameliorated endothelium function and decreased the arterial pressure [16]. Thus, interaction of O 2 ¯ with NO should primary have place in extracellular space [17].…”

Section: Extracellular Superoxide Dismutasementioning

confidence: 99%

Enzymatic Antioxidants: Next Phase of Pharmacological Effort to Fight Oxidative Stress?

Maksimenko¹,

Vavaev²,

Tischenko³

2010

TOPROCJ

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Abstract:The focus in the research of antioxidants is notably displaced in favour of research of enzyme derivatives. Extracellular superoxide dismutase (EC-SOD) is of the particular interest, as it demonstrates in vivo the protective action against development of atherosclerosis, hypertension, heart failure, diabetes mellitus. The reliable association of coronary artery disease with the decreased level of heparin-released EC-SOD was established in clinical researches. To base and develop antioxidant therapy, various SOD isozymes, catalase (CAT), the methods of experimental gene therapy, combined application of SOD-and CAT-activities are used. Covalent bienzyme SOD -CHS -CAT conjugate (where CHS -chondroitin sulphate) showed in the experimental trials its high efficacy as the antithrombotic agent. Pre-clinical research data approve the reliable option to gain for it the status of drug candidate. The trend to use the components of glycocalyx and extracellular matrix for target delivery of medical substances is evident. Development of new enzyme antioxidants for therapeutical destination is closely connected with becoming and progress of medical biotechnology, pharmaceutical industry, bioeconomy.

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Endothelium‐targeted Gene and Cell‐based Therapy for Cardiovascular Disease

Melo¹,

Pachori²,

Gnecchi³

et al. 2007

Endothelial Dysfunctions in Vascular Disease

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Gene Transfer of Extracellular Superoxide Dismutase Reduces Arterial Pressure in Spontaneously Hypertensive Rats

Cited by 149 publications

References 59 publications

Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Gene transfer of extracellular superoxide dismutase improves relaxation of aorta after treatment with endotoxin

Enzymatic Antioxidants: Next Phase of Pharmacological Effort to Fight Oxidative Stress?

Endothelium‐targeted Gene and Cell‐based Therapy for Cardiovascular Disease

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