Inhibition of collar-induced carotid atherosclerosis by recombinant apoA-I cysteine mutants in apoE-deficient mice.
The previous studies in our laboratory revealed that seven cysteine mutants of apolipoprotein A-I (apoA-I) have different structural features and biological activities in vitro and in vivo. To investigate the potential cardioprotective effects of apolipoprotein A-I(N74C) [apoA-I(N74C)], we examined the anti-inflammatory, antioxidant, and antiatherosclerotic effects of this cysteine mutant in a rapid atherosclerosis model induced by perivascular carotid collar placement in apoE⁻/⁻ mice. Lipid-free apoA-I(N74C) showed a significant increased antioxidant potency in low density lipoprotein (LDL) oxidation in vitro and reduced intracellular lipid accumulation in THP-1-derived macrophages, relative to wild-type apoA-I (apoA-Iwt). Mice injected with recombinant HDL (rHDL) reconstituted with apoA-I(N74C) (named rHDL74) through tail veins (40 mg/kg of body weight, three injections) had a significant lower level of serum interleukin-6 (IL-6) and enhanced serum antioxidation compared with mice receiving rHDL reconstituted with apoA-Iwt (named rHDLwt). Moreover, compared with rHDLwt, the rHDL74 in vivo injection resulted in a significant decrease in plaque size, ratio of aorta intima to media, arterial remodeling, and macrophage content in lesions. In summary, intravenous injection with rHDL74 reconstituted with apoA-I cysteine mutant apoA-I (N74C) dramatically delays the development of atherosclerosis induced by perivascular carotid collar placement and reduces vascular remodeling in the carotid artery in apoE⁻/⁻ mice.
Zhang
Xinbo
X
National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Zhu
Xuewei
X
Chen
Baosheng
B
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010084:Oxidation-Reduction / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D000975:Antioxidants; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D016207:Cytokines; D015850:Interleukin-6; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011994:Recombinant Proteins
Methods Enzymol. 1990;186:421-31
2233309
Circulation. 2005 Aug 16;112(7):976-83
16087797
J Lipid Res. 1999 Feb;40(2):345-53
9925665
J Lipid Res. 1988 Nov;29(11):1405-15
3149286
Circulation. 2001 Jun 26;103(25):3047-50
11425766
J Biol Chem. 1983 Feb 25;258(4):2508-13
6401735
Arterioscler Thromb Vasc Biol. 2000 Oct;20(10):2243-7
11031210
J Atheroscler Thromb. 2009 Jun;16(3):217-29
19638715
Nat Rev Cardiol. 2010 Feb;7(2):77-86
20065951
J Clin Invest. 1990 Aug;86(2):379-84
2200802
J Lipid Res. 2005 Jun;46(6):1303-11
15805548
Circulation. 2001 Feb 27;103(8):1164-70
11222482
Circulation. 1998 Mar 3;97(8):780-5
9498542
Infect Immun. 1995 Jan;63(1):253-8
7528733
Arterioscler Thromb Vasc Biol. 1999 Oct;19(10):2364-7
10521365
Eur J Clin Invest. 2006 Dec;36(12):875-82
17087782
Circulation. 2001 Jan 2;103(1):108-12
11136694
Circulation. 2003 May 27;107(20):2551-4
12742990
Biochim Biophys Acta. 2006 Dec;1761(12):1401-9
17110163
Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):650-7
14764423
Circulation. 2005 Mar 29;111(12):1543-50
15781735
Anal Biochem. 1996 Jul 15;239(1):70-6
8660627
Circulation. 2004 Nov 30;110(22):3493-500
15557373
J Lipid Res. 1982 Jul;23(5):680-91
6811681
Am J Med. 1977 May;62(5):707-14
193398
J Lipid Res. 2008 Aug;49(8):1640-5
18458046
Exp Mol Med. 2009 Jun 30;41(6):417-28
19322022
Atherosclerosis. 2007 Nov;195(1):e112-24
17482195
Circ Res. 2004 Oct 15;95(8):764-72
15486323
N Engl J Med. 1999 Jan 14;340(2):115-26
9887164
J Am Coll Cardiol. 2006 Mar 7;47(5):992-7
16516083
Circulation. 2005 Mar 22;111(11):1422-30
15781753
J Exp Med. 1996 Nov 1;184(5):1601-8
8920850
Circulation. 2003 Feb 11;107(5):762-8
12578882
Biochemistry. 2001 Feb 13;40(6):1710-8
11327831
Adv Protein Chem. 1994;45:303-69
8154372
Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):525-30
10073953
JAMA. 2003 Nov 5;290(17):2292-300
14600188
Lancet. 1977 May 7;1(8019):965-8
67464
Mol Cells. 2009 Mar 31;27(3):291-7
19326075
Arterioscler Thromb Vasc Biol. 1998 Oct;18(10):1617-24
9763535
Arterioscler Thromb Vasc Biol. 1999 Feb;19(2):378-83
9974422
Atherosclerosis. 1997 Jan 3;128(1):121-8
9051205
Circulation. 2001 Apr 17;103(15):1949-54
11306522