Published online before print February 3, 2005, doi: 10.1161/01.ATV.0000158383.65277.2b
© 2005 American Heart Association, Inc.
Atherosclerosis & Lipoproteins |
Serum Amyloid A and Lipoprotein Retention in Murine Models of Atherosclerosis
From the Divisions of Cardiology (K.D.O., T.O.M., K.E., E.A.K., R.L.) and Metabolism, Endocrinology, and Nutrition (K.L., A.C.), Department of Medicine and Department of Pathobiology (E.A.K., R.C.L.), University of Washington, Seattle; Massachusetts General Hospital (V.K.), Boston, Mass; and Hope Heart Program at the Bennaroya Research Institute (T.N.W.), Seattle, Wash; and Department of Medicine (F.C.d.B.), University of Kentucky, Lexington.
Correspondence to Kevin D. O’Brien, MD, Division of Cardiology, Box 356422, University of Washington, Seattle, WA 98195-6422. E-mail cardiac{at}u.washington.edu
Objective— Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk in humans. Because SAA associates primarily with lipoproteins in plasma and has proteoglycan binding domains, we postulated that SAA might mediate lipoprotein retention on atherosclerotic extracellular matrix.
Methods and Results— Immunohistochemistry was performed for SAA, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and perlecan on proximal aortic lesions from chow-fed low-density lipoprotein receptor (LDLR)–/– and apoE–/– mice euthanized at 10, 50, and 70 weeks. SAA was detected on atherosclerotic lesion extracellular matrix at all time points in both strains. SAA area correlated highly with lesion areas (apoE–/–, r=0.76; LDLR–/–, r=0.86), apoA-I areas (apoE–/–, r=0.88; LDLR–/–, r=0.80), apoB areas (apoE–/–, r=0.74; LDLR–/–, r=0.89), and perlecan areas (apoE–/–, r=0.83; LDLR–/–, r=0.79) (all P<0.0001). In vitro, SAA enrichment increased high-density lipoprotein (HDL) binding to heparan sulfate proteoglycans, and immunoprecipitation experiments using plasma from apoE–/– and LDLR–/– mice demonstrated that SAA was present on both apoA-I–containing and apoB-containing lipoproteins.
Conclusions— In chow-fed apoE–/– and LDLR–/– mice, SAA is deposited in murine atherosclerosis at all stages of lesion development, and SAA immunoreactive area correlates highly with lesion area, apoA-I area, apoB area, and perlecan area. These findings are consistent with a possible role for SAA-mediated lipoprotein retention in atherosclerosis.
In chow-fed apoE–/– and LDLR–/– mice, serum amyloid A (SAA) is deposited at all stages of atherosclerotic lesion development and SAA immunoreactive area correlates highly with areas for lesions, apoA-I, apoB, and perlecan. These findings are consistent with the hypothesis that SAA may participate in atherosclerotic lesion lipoprotein retention.
Key Words: atherosclerosis • lipoproteins • perlecan • proteoglycans • serum amyloid A
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