Elevated low density lipoproteins (LDL) cholesterol and decreased high density lipoproteins (HDL) cholesterol are two defined risk factors associated with increased coronary artery disease (CAD). Conversely, low levels of LDL cholesterol and high levels of HDL cholesterol are associated with a decreased risk of CAD. Furthermore, pharmacologic intervention studies with the lipid lowering agents nicotinic acid and cholestyramine demonstrate that LDL cholesterol lowering is associated with a decreased risk of CAD. The projects summarized here are concerned with treatment or prevention of CAD by developing new strategies for lowering LDL cholesterol and to better understand HDL cholesterol physiology so that new approaches can be developed to increase HDL cholesterol. With respect to lowering LDL cholesterol, a means of decreasing the synthesis of the major protein associated with the LDL particle transport, apoB, is being developed using the agent vanadate. Vanadate appears to decrease apoB protein biosynthesis, decrease apoB mRNA levels and cause the formation of an apoB isoprotein that has a much shorter half life. Other currently used agents decrease LDL cholesterol through other mechanisms, so this approach could provide an additional treatment modality. With respect to increasing HDL cholesterol, our studies evaluated the site(s) of synthesis in man of the two major proteins in HDL, apoA-I and apoA-II, and found that the liver made both apolipoproteins, whereas the small intestine only made apoA-I. Since the apparent best HDL predictor of protection from CAD appears to be the quantity of HDL particles containing only apoA-I, the suggestion is that the small intestine may be the best target for intervention to selectively increase apoA-I only HDL particles.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL002033-02
Application #
3843300
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost
Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
United States
Zip Code