Extracellular superoxide dismutase (EC-SOD) is a recently discovered member of a family of superoxide dismutase (SOD) enzymes. It is highly expressed in the lung and blood vessels. Superoxide radicals can attenuate the relaxing properties of endothelium derived relaxing factor (EDRF) and initiate reactive oxygen species. Because of EC-SOD's unique location and function, it is likely regulated. We propose that variable intracellular proteolytic processing of EC-SOD can lead to two distinct products: (1) a constituitively produced uncleaved EC-SOD (cEC-SOD) and (2) an inducible proteolytically cleaved EC-SOD (iEC-SOD). We intend to show that the primary role of cEC-SOD is to protect nitric oxide signaling in vasculature and the primary role of iEC-SOD is to protect the extracellular space from superoxide initiated damage during inflammation. Multiple approaches will elucidate these potential roles of cEC-SOD and iEC-SOD: a) EC-SOD knockout and overexpressing transgenic mice will be studied during models of lung inflammation and in aortic ring preparations; b) multiple rodent species which have variable amounts of aortic cEC-SOD activity will be used to show a correlation between cEC-SOD activity and protection of the nitric acid response; c) SOD mimetic drugs will be added to aortic ring preparations in these species to see if vasculature from a species with low cEC-SOD activity can be made to react like a species with high cEC-SOD activity; d) cell culture experiments will reveal which inflammatory cytokines are responsible for inducing iEC-SOD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL010220-01
Application #
6012737
Study Section
Special Emphasis Panel (ZRG1-RAP (01))
Project Start
1999-12-23
Project End
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80206