Circulation. 2004;109:647-655
Published online before print January 26, 2004, doi: 10.1161/01.CIR.0000114526.50618.24
Published online before print January 26, 2004, doi: 10.1161/01.CIR.0000114526.50618.24
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(Circulation. 2004;109:647-655.)
© 2004 American Heart Association, Inc.
Basic Science Reports |
C-Reactive Protein Accelerates the Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice
From the Division of Diabetes, Endocrinology and Metabolism, Departments of Medicine and Molecular & Cellular Biology, (A.P., K.W.S.K., L.L., V.Y., L.C.) Baylor College of Medicine, Houston, Tex, and Division of Clinical Immunology and Rheumatology, Department of Medicine, (M.A.M., A.J.S.) University of Alabama at Birmingham, Birmingham, Ala.
Correspondence to Dr Lawrence Chan, Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine N510.20, One Baylor Plaza, Houston, TX 77030. E-mail lchan{at}bcm.tmc.edu
Received November 6, 2003; revision received December 5, 2003; accepted December 10, 2003.
Background— Plasma C-reactive protein (CRP) concentration is a strong predictor of atherosclerosis. However, to date, there is no in vivo evidence that CRP is proatherogenic.
Methods and Results— We studied the effect of human CRP transgene (tg) expression, under basal and turpentine-stimulated conditions, on atherosclerosis in apolipoprotein (apo) E-/- mice. Aortic atherosclerotic lesions in 29-week-old male mice were 48% larger (P<0.02) in turpentine-treated mice and 34% larger (P<0.05) in untreated CRPtg+/0/apoE-/- mice. Turpentine treatment per se did not affect the extent of atherosclerosis in CRP transgenic or nontransgenic apoE-/- mice. Transgenic mice exhibited lower plasma complement C3 but increased deposition of CRP and C3 in the lesions, which suggests that CRP stimulated activation of complement within the lesion. There was more intense and widespread vascular cell adhesion molecule-1 and collagen staining in the lesions of CRPtg+/0/apoE-/- mice than in CRPtg0/0/apoE-/- littermates. Lesions of CRPtg+/0/apoE-/- mice contained increased angiotensin type 1 receptor (AT1-R) transcripts and displayed increased AT1-R immunostaining compared with those of CRPtg0/0/apoE-/- mice. There was no difference in blood pressure in the 2 types of mice, which indicates that the proatherogenic effect of CRP-associated AT1-R overexpression is local and not mediated by its hypertensive properties.
Conclusions— Human CRP transgene expression causes accelerated aortic atherosclerosis in apoE-/- mice. CRP was detected in the lesion, which was associated with increased C3 deposition and increased AT1-R, vascular cell adhesion molecule-1, and collagen expression. These data document a proatherogenic role for CRP in vivo.
Key Words: C-reactive protein • angiotensin • atherosclerosis
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