450
chapter
2 0
Lipids III: Plasma Lipoproteins
H M G -C o A
F I G U R E 2 0 - 1 3
Competitive inhibitors of HMG-CoA reductase, the rate-controlling
enzyme of cholesterol biosynthesis. Note the similarity in structures.
Statins are fungal derivatives or chemically
-
synthesized therapeutic agents (Chapter 19). The
structure of a statin is compared to that of HMG-CoA
in Figure 20-13. Other properties of statins include
activation of endothelial nitric oxide synthase,
decreased fibrinogen levels and viscosity, diminished
uptake of aggregated LDL by vascular smooth cells, a
modest increase in HDL cholesterol levels, and an
enhanced immune tolerance after transplantation.
Because of various biological effects, statin therapy
can reduce the effects of both coronary and
cerebrovascular diseases and can decrease the need
for coronary artery bypass surgery and angioplasty.
Since statins inhibit a key step in a multifunctional
cholesterol biosynthetic pathway, their long-term
toxicity is not known (Chapter 19).
A combination of bile acid sequestrants with nicotinic
acid or probucol or an HMG-CoA reductase inhibitor can
be used to produce synergistic effects in lowering plasma
lipoprotein levels, particularly LDL. The efficacy of drug
treatment was shown in a recent study in which lovas-
tatin and colestipol were used to reduce cholesterol levels
in men with CHD. The rate of progression of coronary
lesions was decreased and that of regression increased.
These changes also were associated with reduced cardio-
vascular abnormalities.
Treatment of homozygous FH individuals with diet or
drug therapy is not effective. Other modes of therapy for
this condition include frequent plasma exchange and cre-
ation of a portacaval shunt. In one patient, liver transplanta-
tion was highly successful in reducing plasma LDL levels,
underscoring the important role of the liver in cholesterol
homeostasis.
In patients with blocked coronary blood vessels, coro-
nary artery bypass grafting or angioplasty may be required.
A potential new therapy involves agents that promote the
formation of new blood vessels (angiogenesis). However,
drugs that interfere with the formation of new blood ves-
sels (angiogenesis inhibitors) may have a promising fu-
ture in the treatment of cancer since they can cut off blood
supply to tumors.
Supplemental Readings and References
M. A. Austin, B. McKnight, K. L. Edwards, et al.: Cardiovascular disease
mortality in familial forms of hypertriglyceridemia: A 20-year prospective
study.
Circulation
1 0 1 , 2777 (2000).
M. Bodzioch, E. Orso, J. Klucken, et al.: The gene encoding ATP-binding
cassette transporter I is mutated in Tangier disease.
Nature Genetics
22,
347(1999).
A.G. Bostom, H. Silbershatz, 1. H. Rosenberg, et al.: Nonfasting plasma total
homocysteine levels and all-cause and cardiovascular disease mortality in
elderly Framingham men and women.
Archives of Internal Medicine
1 5 9 ,
1077(1999).
M. N. Diaz, B. Frei, J. A. Vita, et al.: Antioxidants and atherosclerotic heart
disease.
New England Journal of Medicine
337,408 (1997).
J. J.Genest Jr.,S. S. Martin-Munley, J. R. McNamara, etal.: Familial lipopro-
tein disorders in patients with premature coronary artery disease.
Circu-
lation
8 5 , 2025 (1992).
A. M. GoHo: Prognostic and therapeutic significance of low-levels of high-
density lipoprotein cholesterol.
Archives of Internal Medicine
1 5 9 , 1038
(1999).
D. J. Gordon and В. M. Rifkind: High-density lipoprotein—The clinical
implications of recent studies.
New England Journal of Medicine
321,
1311 (1989).
A. Graham, D. G. Hassall, S. Rafique, and J. S. Owen: Evidence for a
paraoxonase-independent inhibition of low-density lipoprotein oxidation
by high-density lipoprotein.
Atherosclerosis
1 3 5 , 193 (1997).
S. M. Grundy: Cholesterol and coronary heart disease.
Archives of Internal
Medicine
1 5 7 , 1177(1997).
C. R. Harper and T. A. Jacobson: New perspectives on the management of
low levels of high-density lipoprotein cholesterol.
Archives of Internal
Medicine
1 5 9 , 1049 (1999).
R. H. Knopp: Drug treatment of lipid disorders.
New England Journal of
Medicine
3 4 1 ,498 (1999).
S. Kochi, F. Fresser, E. Lobentanz, et al.: Novel interaction of apolipopro-
tein(a) with /3-2 glycoprotein I mediated by the kringle IV domain.
Blood
9 0 , 1482(1997).
J. A. Kuivenhoven, J. W. Jukema, A. H. Zwinderman, et al.: The role of a
common variant of the cholesteryl ester transfer protein gene in the pro-
gression of coronary atherosclerosis.
New England Journal of Medicine
3 3 8 , 86(1998).
A. Maitra, S. V. Hirany, and I. Jialal: Comparison of two assays for measuring
LDL cholesterol.
Clinical Chemistry
4 3 , 1040 (1997).
M. E. Mendelsohn and R. H. Karas: The protective effects of estrogen on
the cardiovascular system.
New England Journal of Medicine
340, 1801
(1999).
C. N. B. Merz, A. Rozanski, and J. S. Forrester: The Secondary Prevention
of Coronary Artery Disease.
The American Journal of Medicine
1 0 2 ,572
(1997).
J. J. Repa, S. D. Turley, J-M.A. Lobaccaro, et al.: Regulation of absorption
