Abstract
Superoxide and superoxide-derived oxidants have been hypothesized to be important mediators of postischemic injury. Whereas copper, zinc-superoxide dismutase SOD1, efficiently dismutates superoxide, the has been controversy regarding whether increasing intracellular SOD1 expression would protect against or potentiate cellular injury. To determine whether increased SOD1 protects the heart from ischemia and reperfusion, studies were performed in a newly developed transgenic mouse model in which direct measurement of superoxide, contractile function, bioenergetics, and cell death could performed. Transgenic mice with overexpression of human SOD1 were studied along with matched nontransgenic controls. Immunoblotting and immunohistology demonstrated that total SOD1 expression was increased 10-fold in hearts from transgenic mice compared with nontransgenic controls, with increased expression in both myocytes and endothelial cells. In nontransgenic hearts following 30 min of global ischemia a reperfusion-associated burst of superoxide generation was demonstrated by electron paramagnetic resonance spin trapping. However, in the transgenic hearts with overexpression of SOD1 the burst of superoxide generation was almost totally quenched, and this was accompanied by a 2-fold increase in the recovery of contractile function, a 2.2-fold decrease in infarct size, and a greatly improved recovery of high energy phosphates compared with that in nontransgenic controls. These results demonstrate that superoxide is an important mediator of postischemic injury and that increasing intracellular SOD1 dramatically protects the heart from this injury. Thus, increasing intracellular SOD1 expression may be a highly effective approach to decrease the cellular injury that occurs following reperfusion of ischemic tissues.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4556-4560 |
| Number of pages | 5 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 95 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 14 1998 |
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Keywords
- Electron paramagnetic resonance
- Myocardial infarction
- Nuclear magnetic resonance
- Superoxide radical
- Transgenic model
ASJC Scopus subject areas
- Genetics
- General
Cite this
Overexpression of human copper,zinc-superoxide dismutase (SOD1) prevents postischemic injury. / Wang, Penghai; Chen, Hua; Qin, Honghua; Sankarapandi, Sornampillai; Becher, Mark W.; Wong, Philip Chun; Zweier, Jay L.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 8, 14.04.1998, p. 4556-4560.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Overexpression of human copper,zinc-superoxide dismutase (SOD1) prevents postischemic injury
AU - Wang, Penghai
AU - Chen, Hua
AU - Qin, Honghua
AU - Sankarapandi, Sornampillai
AU - Becher, Mark W.
AU - Wong, Philip Chun
AU - Zweier, Jay L.
PY - 1998/4/14
Y1 - 1998/4/14
N2 - Superoxide and superoxide-derived oxidants have been hypothesized to be important mediators of postischemic injury. Whereas copper, zinc-superoxide dismutase SOD1, efficiently dismutates superoxide, the has been controversy regarding whether increasing intracellular SOD1 expression would protect against or potentiate cellular injury. To determine whether increased SOD1 protects the heart from ischemia and reperfusion, studies were performed in a newly developed transgenic mouse model in which direct measurement of superoxide, contractile function, bioenergetics, and cell death could performed. Transgenic mice with overexpression of human SOD1 were studied along with matched nontransgenic controls. Immunoblotting and immunohistology demonstrated that total SOD1 expression was increased 10-fold in hearts from transgenic mice compared with nontransgenic controls, with increased expression in both myocytes and endothelial cells. In nontransgenic hearts following 30 min of global ischemia a reperfusion-associated burst of superoxide generation was demonstrated by electron paramagnetic resonance spin trapping. However, in the transgenic hearts with overexpression of SOD1 the burst of superoxide generation was almost totally quenched, and this was accompanied by a 2-fold increase in the recovery of contractile function, a 2.2-fold decrease in infarct size, and a greatly improved recovery of high energy phosphates compared with that in nontransgenic controls. These results demonstrate that superoxide is an important mediator of postischemic injury and that increasing intracellular SOD1 dramatically protects the heart from this injury. Thus, increasing intracellular SOD1 expression may be a highly effective approach to decrease the cellular injury that occurs following reperfusion of ischemic tissues.
AB - Superoxide and superoxide-derived oxidants have been hypothesized to be important mediators of postischemic injury. Whereas copper, zinc-superoxide dismutase SOD1, efficiently dismutates superoxide, the has been controversy regarding whether increasing intracellular SOD1 expression would protect against or potentiate cellular injury. To determine whether increased SOD1 protects the heart from ischemia and reperfusion, studies were performed in a newly developed transgenic mouse model in which direct measurement of superoxide, contractile function, bioenergetics, and cell death could performed. Transgenic mice with overexpression of human SOD1 were studied along with matched nontransgenic controls. Immunoblotting and immunohistology demonstrated that total SOD1 expression was increased 10-fold in hearts from transgenic mice compared with nontransgenic controls, with increased expression in both myocytes and endothelial cells. In nontransgenic hearts following 30 min of global ischemia a reperfusion-associated burst of superoxide generation was demonstrated by electron paramagnetic resonance spin trapping. However, in the transgenic hearts with overexpression of SOD1 the burst of superoxide generation was almost totally quenched, and this was accompanied by a 2-fold increase in the recovery of contractile function, a 2.2-fold decrease in infarct size, and a greatly improved recovery of high energy phosphates compared with that in nontransgenic controls. These results demonstrate that superoxide is an important mediator of postischemic injury and that increasing intracellular SOD1 dramatically protects the heart from this injury. Thus, increasing intracellular SOD1 expression may be a highly effective approach to decrease the cellular injury that occurs following reperfusion of ischemic tissues.
KW - Electron paramagnetic resonance
KW - Myocardial infarction
KW - Nuclear magnetic resonance
KW - Superoxide radical
KW - Transgenic model
UR - http://www.scopus.com/inward/record.url?scp=0032516036&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0032516036&partnerID=8YFLogxK
U2 - 10.1073/pnas.95.8.4556
DO - 10.1073/pnas.95.8.4556
M3 - Article
VL - 95
SP - 4556
EP - 4560
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 8
ER -