Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis.

Abstract

BACKGROUND:

Obesity-associated dyslipidemia in humans is associated with increased low-density lipoprotein (LDL) oxidation. Mice with combined leptin and LDL receptor deficiency are obese and show severe dyslipidemia and insulin resistance. We investigated the association between oxidation of apolipoprotein B-containing lipoproteins, high-density lipoprotein (HDL) antioxidant defense, and atherosclerosis in these mice.

METHODS AND RESULTS:

LDL receptor knockout (LDLR-/-), leptin-deficient (ob/ob), double-mutant (LDLR-/-;ob/ob), and C57BL6 mice were fed standard chow. Double-mutant mice had higher levels of non-HDL (P<0.001) and HDL (P<0.01) cholesterol and of triglycerides (P<0.001). They also had higher oxidative stress, evidenced by higher titers of autoantibodies against malondialdehyde-modified LDL (P<0.001). C57BL6 and ob/ob mice had no detectable lesions. Lesions covered 20% of total area of the thoracic abdominal aorta in double-mutant mice compared with 3.5% in LDLR-/- mice (P<0.01). Higher macrophage homing and accumulation of oxidized apolipoprotein B-100-containing lipoproteins were associated with larger plaque volumes in the aortic root of double-mutant mice (P<0.01). The activity of the HDL-associated antioxidant enzymes paraoxonase and lecithin:cholesterol acyltransferase (LCAT) (ANOVA; P<0.0001 for both) was lower in double-mutant mice. Adenovirus-mediated LCAT gene transfer in double-mutant mice increased plasma LCAT activity by 64% (P<0.01) and reduced the titer of autoantibodies by 40% (P<0.01) and plaque volume in the aortic root by 42% (P<0.05) at 6 weeks.

CONCLUSIONS:

Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice are associated with increased oxidative stress and impaired HDL-associated antioxidant defense, evidenced by decreased paraoxonase and LCAT activity. Transient LCAT overexpression was associated with a reduction of oxidative stress and atherosclerosis.

• Authors: Ann Mertens, Peter Verhamme, John K Bielicki, Michael C Phillips, Rozenn Quarck, Wim Verreth, Dominique Stengel, Ewa Ninio, Mohamad Navab, Bharti Mackness, Mike Mackness, Paul Holvoet
• Journal: Circulation (Circulation) Vol. 107 Issue 12 Pg. 1640-6 (Apr 01 2003) ISSN: 1524-4539 [Electronic] United States
• PMID: 12668499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antioxidants
• Cell Adhesion Molecules
• Lipids
• Lipoproteins, HDL
• Lipoproteins, LDL
• Receptors, LDL
• oxidized low density lipoprotein
• Cholesterol
• Phosphatidylcholine-Sterol O-Acyltransferase
• Esterases
• Aryldialkylphosphatase

Topics

• Animals
• Antioxidants (metabolism)
• Aorta (metabolism, pathology)
• Arteriosclerosis (etiology, metabolism, pathology, therapy)
• Aryldialkylphosphatase
• Cell Adhesion Molecules (biosynthesis)
• Cell Line
• Cell Movement
• Cholesterol (blood, metabolism)
• Esterases (metabolism)
• Hyperlipidemias (complications)
• Lipids (blood)
• Lipoproteins, HDL (physiology)
• Lipoproteins, LDL (metabolism)
• Macrophages (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Obese
• Oxidation-Reduction
• Oxidative Stress
• Phosphatidylcholine-Sterol O-Acyltransferase (genetics, metabolism)
• Receptors, LDL (genetics)