The Protective Capacity of Normal High Density Lipoprotein Against Lipid Oxidation

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Article Information:


Group: 2003
Subgroup: Volume 1, Issue 1, Winter
Date: March 2003
Type: Editorial
Start Page: 3
End Page: 5

Authors:

  • A Lahiji
  • Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, USA
  • Mohammad Navab
  • Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, USA

      Correspondence:

      Affiliation: Division of Cardiology, David Geffen School of Medicine, University of California
      City, Province: Los Angeles,
      Country: USA
      Tel: -
      Fax: -
      E-mail: nmavab@mednet.ucla.edu

Manuscript Body:


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 ofHDL in vivo. In 1994, Plump et all found that apolipoprotein A-I transgene expression resulted in the reduction of lesion formation in apolipoprotein E knockout mice. Rong and colleagues;' 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 aV 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," 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.r" 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 apoiipoprotein A-I. TI1is 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-I), facilitating the conversion of monocytes to macrophages, and macrophage survival.i providing an explanation for the studies conducted by Shah et al," 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,2where MCP-l 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-lor the infusion of the recombinant apolipoprotein A-I confers stability to the atherosclerotic lesion." Our group has reported evidence indicating that there is a strong association between the inflammatory response of atherosclerotic lesions and LDL-derived oxidized phospholipids." The inverse relationship between HDL and clinical events is well documented. II 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.f'" This hypothesis is further supported by Van Lenten et ai, 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 playa 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: (13)

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