1. Gene transfer of extracellular superoxide dismutase protects against vascular dysfunction with aging Am J Physiol Heart Circ Physiol 290: H2600–H2605, 2006. Kathryn A. Brown, Yi Chu,Donald D. Lund, Donald D. Heistad, and Frank M. Faraci Speaker: 賴小婷 Date:97/08/13

2. Introduction

4. O 2 ． ¯ H 2 0 2 H 2 O+O 2 NO + O 2 ． ¯ ONOO¯ Oxidative stress (Peroxynitrite) DNA damage (Endothelial dysfunction) SOD Calatase GPx SOD ONOO ¯ can induce protein modifications and DNA damage

7. Methods

8. Male Fischer 344 rats ages 4–6 months ( n = 23) Young 29–31 months ( n = 37) Old Plasma analysis ( glucose 、 cholesterol ) Gene transfer of ECSOD and ECSOD△HBD Thoracic aortas ( 95% O2-5% CO2 .37℃) ＊ Vasomotor function (ACh 、 SNP 、 5-HT 、 PE ) ＊ SOD protein expression ＊ Superoxide levels ( O2 ． ¯ )

9. ECSODHBD is identical to ECSOD except that the carboxy-terminal 13-amino-acid segment containing the HBD is deleted . ECSOD is a homotetrameric glycosylated protein (155 kDa) CuZnSOD is a 32-kDa homodimer without glycosylation ( Circ Res . 2003;92:461-468.)

10. Results

11. Fig 1 * Old rats had significantly higher plasma levels of cholesterol than young rats, although the levels of cholesterol were still relatively low There was no significant difference in body weight or plasma glucose (nonfasting) between young and old Fischer 344 rats

12. Acetylcholine Relaxation Vasomotor function ◎ Acetylcholine (ACh) stimulates the endothelial cells to produce a factor, NO, which penetrates into and activates the muscle cells causing relaxation

13. Fig 2 Responses to ACh were significantly improved after adenoviral-mediated gene transfer of human ECSOD Transfection with ECSOD lacking the HBD had no significant effect on responses to ACh in vessels from old rats ACh:Acetylcholine ＊ ACh was used to assess NO-mediated endothelial function

14. Fig 3 Responses to SNP were similar in aortas from young and old rats and were not altered by gene transfer of either form of ECSOD ◎ SNP (sodium nitroprusside) : activates the vessel causing relaxation

15. Fig 4 There were no significant differences in response to serotonin in aortas from young and old rats ◎ 5-HT (5-hydroxytryptamine 、 serotonin) : stimulates smooth muscle cell contraction

16. Fig 5 Gene transfer of either form of ECSOD had no significant effect on the response to phenylephrine ◎ PE (Phenylephrine): stimulates the vessel causing contraction

17. Fig 6 There were no significant differences in the levels of MnSOD and CuZnSOD between groups There was a tendency for MnSOD to be increased in the old rats

18. Fig 7 After gene transfer of ECSOD, superoxide levels from old rats were similar to those in aorta from young rats Superoxide levels

19. Discussion

20. These results suggest : 1 . Vascular dysfunction associated with aging is mediated in part by increased levels of superoxide 2 . Gene transfer of ECSOD reduces vascular superoxide and dysfunction in old rats 3 .Beneficial effects of ECSOD in old rats require the heparin-binding domain (HBD) of ECSOD.

22. ☆ Thanks for your attention