(Circulation. 1999;99:12-14.)
© 1999 American Heart Association, Inc.
Editorial |
Gene Targets and Approaches for Raising HDL
From the Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, and TNO-PG/Gaubius Laboratory, Leiden, The Netherlands (B.J.M.V.), and the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas (J.H.).
Correspondence to Joachim Herz, Department of Molecular Genetics, UT Southwestern, 5323 Harry Hines Blvd, Dallas, TX 75235-9046. E-mail herz@utsw.swmed.edu
Key Words: Editorials • genes • cholesterol • atherosclerosis
Susceptibility to
atherosclerosis in humans is inversely correlated to
the concentration of plasma HDL.1 Over the past 10 years,
the question of how HDL plays a direct role in the prevention of
atherosclerosis has been the focus of intense research.
The antiatherogenic effect of HDL may involve (1) promoting reverse
cholesterol transport, during which excess
cholesterol is routed from extrahepatic tissues back to the
liver for elimination or reuse; (2) inhibition of lipoprotein
oxidation; and (3) direct protection of the vessel wall from damages.
These issues and other questions involving HDL metabolism
and its role in atherosclerosis have been successfully
addressed by use of mice in which genes believed to participate in HDL
structure, metabolism, and its protective action on the
vessel wall are overexpressed or inactivated by gene
targeting. The ultimate goal is to apply this knowledge to a
therapeutic purpose, eg, increasing HDL levels in patients suffering
from atherosclerosis. A few years ago, a start was made
to explore gene therapeutic approaches directed at manipulating the
expression of genes that increase HDL or decrease LDL levels.
Adenoviruses have been most commonly used for the delivery of genes to
various target tissues in vivo. Still, considerable advances will have
to be made until safe, stable, and prolonged expression of exogenous
genes may someday be achieved in humans. Here, we briefly summarize the
insights gained on HDL metabolism and the development and
progression of atherosclerosis by overexpression or
inactivation of genes, primarily in mice. We also summarize and discuss
the
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