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The
Protective Capacity of Normal High Density Lipoprotein Against Lipid
Oxidation
Lahiji A, Navab M.
Division of Cardiology, David Geffen School of
Medicine, University of California, Los Angeles, USA
Correspondence: Mohammad Navab, Division of
Cardiology, David Geffen School of Medicine, University of California,
Los Angeles, 90095-1679. E-mail:
mnavab@mednet.ucla.edu
High density lipoprotein (HDL) acts as a powerful endogenous
defense mechanism against atherogenesis. Apolipoprotein A-I is a central
component of HDL that, when present, leads to the formation of HDL in
vivo. In 1994, Plump et al1 found that apolipoprotein A-I transgene
expression resulted in the reduction of lesion formation in
apolipoprotein E knockout mice. Rong and colleagues,2 using a transplant
model, demonstrated, that apolipoprotein A-I transgene expression can
significantly change the structure and composition of advanced
atherosclerotic plaques. Portions of aorta with advanced lesions were
surgically removed from apolipoprotein E knockout mice and transplanted
into the aortas of syngeneic mice, maintained on a chow diet. The
recipient mice expressing the apolipoprotein A-I transgene had lesions
with dramatically different characteristics with an 80% decrease in
lesion macrophage areas and 300% increase in smooth muscle cell content.
Reis et al,3 reported a near complete regression of atherosclerotic
lesions when portions of aorta with advanced lesions from apolipoprotein
E knockout mice on a Western diet were transplanted into the aortas of
wild-type mice. Shah et al,4 found a 40-50% reduction of plaque
cholesterol and 29-36% reduction of plaque macrophage content in
apolipoprotein E knockout mice, maintained on an atherogenic diet,
within 48 hours of injection with a single high dose of recombinant
apolipoprotein A-I, indicating that human apolipoprotein A-I can rapidly
alter the macrophage and cholesterol content of lesions. Our group found
that “seeding molecules”, the products of oxidation of linoleic acid and
arachidonic acid, essential for the oxidation of LDL by human artery
wall cells, can be rapidly removed from LDL and from artery walls cells
by human apolipoprotein A-I and synthetic apolipoprotein A-I mimetic
peptides.5,6 We also found that LDL from mice injected with human
apolipoprotein A-I became resistant to oxidation by aortic endothelial
and smooth muscle cells within 3 to 6 hours of apoA-I injection. Humans
infused with human apolipoprotein A-I phospholipid disks were found to
have LDL that was resistant to oxidation by artery wall cells within 6
hours of the infusion. With our collaborators, Garber, Anantharamaiah
and colleagues, we observed that HDL’s ability to inhibit LDL oxidation
by human artery wall cells could be restored in mice injected daily with
a synthetic class A synthetic peptide analogue of apolipoprotein A-I.
This analogue also protected the mice from atherosclerosis induced by a
high fat, high cholesterol diet.7
We have hypothesized that human apo-lipoprotein A-I could be working
to inhibit the oxidation of LDL by preventing the formation and by
removing LDL-derived oxidized phospholipids which play roles in
stimulating artery wall cells’ production of substances promoting
monocyte migration, such as monocyte chemoattractant protein (MCP-1),
facilitating the conversion of monocytes to macrophages, and macrophage
survival,8 providing an explanation for the studies conducted by Shah et
al,4 and Rong et al,2 where macrophage content was altered by
apolipoprotein A-I. This explanation is further supported in a study
conducted by Rong et al,2 where MCP-1 was reduced in lesions
transplanted in mice expressing the human apolipoprotein A-I transgene.
It appears that it can be predicted that the net effect of the
transgenic expression of apolipoprotein A-I or the infusion of the
recombinant apolipoprotein A-I confers stability to the atherosclerotic
lesion.9 Our group has reported evidence indicating that there is a
strong association between the inflammatory response of atherosclerotic
lesions and LDL-derived oxidized phospholipids.10 The inverse
relationship between HDL and clinical events is well documented.11
However, HDL has been described as anti-inflammatory in the basal state
and pro-inflammatory during an acute phase response, suggesting that
perhaps HDL and LDL-derived oxidized phospholipids are involved in
nonspecific innate immunity.8,10 This hypothesis is further supported by
Van Lenten et al, who reported that HDL, during an acute influenza A
infection in mice and during elective surgery in humans, did not retain
its anti-inflammatory properties.12,13
In patients with diabetes, it has been observed that HDL does not
have the normal capacity to protect against lipid oxidation. This can be
crucial in terms of the protection of lipoproteins against oxidation,
and can apply to the oxidation of VLDL, LDL and even to HDL itself.
Reverse cholesterol transport in HDL and lipid oxidation may be
linked to the multifactorial regulation of an inflammatory response in
atherosclerotic lesions. HDL may play a role in atherosclerotic lesion
dynamics and serve as a marker for clinical events. Determination of HDL
function and protective capacity may prove to be a valuable predictive
test.
References
1. Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene
expression increases high density lipoprotein and suppresses
atherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad
Sci U S A 1994; 91: 9607-11.
2. Rong JX, Li J, Reis ED, Choudhury RP, Dansky HM, Elmalem VI, et
al. Elevating high-density lipoprotein cholesterol in apolipoprotein
E-deficient mice remodels advanced atherosclerotic lesions by decreasing
macrophage and increasing smooth muscle cell content. Circulation 2001;
104: 2447-52.
3. Reis ED, Li J, Fayad ZA, Rong JX, Hansoty D, Aguinaldo JG, et al.
Dramatic remodeling of advanced atherosclerotic plaques of the
apolipoprotein E-deficient mouse in a novel transplantation model. J
Vasc Surg 2001; 34: 541-7.
4. Shah PK, Yano J, Reyes O, Chyu KY, Kaul S, Bisgaier CL, et al.
High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue
cholesterol and rapidly reduces plaque lipid and macrophage content in
apolipoprotein e-deficient mice. Potential implications for acute plaque
stabilization. Circulation 2001; 103: 3047-50.
5. Navab M, Hama SY, Cooke CJ, Anantharamaiah GM, Chaddha M, Jin L,
et al. Normal high density lipoprotein inhibits three steps in the
formation of mildly oxidized low density lipoprotein: step 1. J Lipid
Res 2000; 41: 1481-94.
6. Navab M, Hama SY, Anantharamaiah GM, Hassan K, Hough GP, Watson
AD, et al. Normal high density lipoprotein inhibits three steps in the
formation of mildly oxidized low density lipoprotein: steps 2 and 3. J
Lipid Res 2000; 41: 1495-1508.
7. Garber DW, Datta G, Chaddha M, Palgunachari MN, Hama SY, Navab M,
et al. A new synthetic class A amphipathic peptide analogue protects
mice from diet-induced atherosclerosis. J Lipid Res 2001; 42:545-52.
8. Navab M, Berliner JA, Watson AD, Hama SY, Territo MC, Lusis AJ, et
al. The Yin and Yang of oxidation in the development of the fatty
streak. A review based on the 1994 George Lyman Duff Memorial Lecture.
Arterioscler Thromb Vasc Biol 1996; 16:831-42.
9. Libby P. Current concepts of the pathogenesis of the acute
coronary syndromes. Circulation 2001; 104: 365-72.
10. Navab M, Berliner JA, Subbanagounder G, Hama S, Lusis AJ,
Castellani LW, et al. HDL and the inflammatory response induced by
LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Biol 2001;
21: 481-8.
11. Miller GJ, Miller NE. Plasma-high-density-lipoprotein
concentration and development of ischaemicheart-disease.,Lancet 1975; 1:
16-9.
12. Van Lenten BJ, Wagner AC, Nayak DP, et al. High-density
lipoprotein loses its anti-inflammatory properties during acute
influenza A infection. Circulation 2001; 103: 2283-88.
13. Van Lenten BJ, Hama SY, deBeer FC, et al. Anti-inflammatory HDL
becomes pro-inflammatory during the acute phase response. J Clin Invest
1995; 96: 2758-67.
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