Novel HDL-directed pharmacotherapeutic strategies.
The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights have fueled the development of HDL-targeted drugs, which can be classified among four different therapeutic approaches: directly augmenting apolipoprotein A-I (apo A-I) levels, such as with apo A-I infusions and upregulators of endogenous apo A-I production; indirectly augmenting apo A-I and HDL-cholesterol levels, such as through inhibition of cholesteryl ester transfer protein or endothelial lipase, or through activation of the high-affinity niacin receptor GPR109A; mimicking the functionality of apo A-I with apo A-I mimetic peptides; and enhancing steps in the reverse cholesterol transport pathway, such as via activation of the liver X receptor or of lecithin-cholesterol acyltransferase.
Division of Cardiovascular Medicine, University of Pennsylvania, Penn Tower, 6th Floor, 3400 Spruce Street, Philadelphia, PA 19104, USA. emil.degoma@uphs.upenn.edu
Emil M
EM
Degoma
Daniel J
DJ
Rader
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D008076:Cholesterol, HDL / Q000097:blood; D050171:Dyslipidemias / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D050356:Lipid Metabolism / Q000187:drug effects; D018716:Molecular Mimicry; D016896:Treatment Outcome
C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D015415:Biomarkers; D008076:Cholesterol, HDL; D000960:Hypolipidemic Agents
Cardiol Clin. 2008 Nov;26(4):537-46
18929230
N Engl J Med. 2010 Dec 16;363(25):2406-15
21082868
Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):2020-8
9351367
J Biol Chem. 1999 Dec 24;274(52):36912-20
10601244
J Clin Invest. 2006 Apr;116(4):1052-62
16543947
Circulation. 1995 May 15;91(10):2528-40
7743614
Circulation. 2003 Apr 1;107(12):1640-6
12668499
J Clin Invest. 2010 Aug;120(8):2910-9
20664170
Circulation. 2008 Feb 5;117(5):678-85
18212282
Cardiovasc Diabetol. 2007 May 02;6:15
17475009
Nature. 2000 Jul 13;406(6792):203-7
10910363
J Biol Chem. 2004 Jul 2;279(27):27941-7
15090553
Atherosclerosis. 2010 Feb;208(2):537-42
19698944
Circulation. 2005 Mar 29;111(12):1543-50
15781735
J Am Coll Cardiol. 2008 Jun 10;51(23):2199-211
18534265
N Engl J Med. 2007 Nov 22;357(21):2180-3
17984168
Gene. 2000 Feb 8;243(1-2):93-103
10675617
Arterioscler Thromb Vasc Biol. 2000 May;20(5):1323-9
10807749
J Clin Invest. 2006 May;116(5):1435-42
16670775
Am J Cardiol. 2009 Jul 1;104(1):74-81
19576324
Circulation. 2005 Aug 9;112(6):879-84
16061733
J Am Coll Cardiol. 2010 Jun 15;55(24):2721-6
20399059
PLoS Med. 2006 Feb;3(2):e22
16354105
Arterioscler Thromb Vasc Biol. 2002 Jul 1;22(7):1148-54
12117730
Arterioscler Thromb Vasc Biol. 2008 Sep;28(9):1672-8
18566298
J Lipid Res. 2010 Feb;51(2):416-21
19671930
Lancet. 2007 Dec 8;370(9603):1907-14
18068514
Circulation. 2004 Sep 14;110(11):1418-23
15337694
N Engl J Med. 2009 Jun 11;360(24):2503-15
19502645
J Clin Invest. 1990 Apr;85(4):1234-41
2318976
JAMA. 2004 Mar 3;291(9):1071-80
14996776
Biochem Biophys Res Commun. 1999 Oct 22;264(2):465-8
10529386
Circulation. 2009 Aug 18;120(7):628-35
19687369
Lancet. 2007 Jul 14;370(9582):153-160
17630038
Circulation. 2004 Dec 7;110(23):3512-7
15537681
J Lipid Res. 2008 Feb;49(2):369-75
17986713
N Engl J Med. 2007 Nov 22;357(21):2109-22
17984165
J Clin Invest. 1979 May;63(5):858-67
221531
PLoS One. 2010 Apr 14;5(4):e10181
20418958
Int J Biol Sci. 2009 Oct 09;5(7):637-46
19847320
J Lipid Res. 2007 Sep;48(9):1915-23
17570869
J Clin Invest. 2003 Feb;111(3):357-62
12569161
Am J Cardiol. 2009 Nov 16;104(10 Suppl):32E-8E
19895942
Nat Genet. 1999 Apr;21(4):424-8
10192396
Eur Heart J. 2009 Jul;30(13):1584-9
19411665
J Am Coll Cardiol. 2010 Jun 8;55(23):2580-9
20513599
J Lipid Res. 2010 Sep;51(9):2739-52
20458119
Cell Metab. 2010 Aug 4;12(2):187-93
20674863
J Biol Chem. 1998 Feb 27;273(9):5033-6
9478952
J Clin Invest. 2003 Feb;111(3):347-55
12569160
J Clin Invest. 2010 Aug;120(8):2651-5
20664168
Circulation. 2002 May 7;105(18):2159-65
11994249
Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):283-9
19965777
J Am Coll Cardiol. 2006 Oct 3;48(7):1459-68
17010811
J Clin Invest. 1977 Oct;60(4):795-807
197124
JAMA. 2007 Apr 18;297(15):1675-82
17387133
Circ Res. 2004 Oct 15;95(8):764-72
15486323
Circulation. 2002 Jan 22;105(3):290-2
11804981
Circulation. 2007 Sep 11;116(11):1267-73
17709636
Circ Res. 2010 Aug 6;107(3):357-64
20558822
Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):781-6
20110577
J Lipid Res. 2009 May;50(5):894-907
19144994
J Biol Chem. 2002 Sep 13;277(37):34182-90
12097330
J Clin Lipidol. 2008 Oct;2(5):375-83
21291763
Am J Physiol Cell Physiol. 2010 Jun;298(6):C1538-48
20219948
Circulation. 2001 Jun 26;103(25):3047-50
11425766
J Lipid Res. 2002 Nov;43(11):1763-9
12401876
J Biol Chem. 2004 Oct 29;279(44):45462-9
15317819
Nat Med. 2003 Mar;9(3):352-5
12563315
J Lipid Res. 2010 Dec;51(12):3443-54
20861162
Curr Opin Lipidol. 2000 Jun;11(3):267-75
10882342
Circulation. 1994 Oct;90(4):1935-41
7923682
Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):2106-12
10978256
Eur Heart J. 2007 Apr;28(8):1012-8
17409111
Circulation. 1994 Mar;89(3):959-68
8124836
Cell. 1998 May 29;93(5):693-704
9630215
Arterioscler Thromb Vasc Biol. 2007 May;27(5):1132-8
17322101
Am J Cardiol. 2009 Nov 16;104(10 Suppl):10E-5E
19895939
J Clin Invest. 2006 Dec;116(12):3090-100
17143322
Am J Cardiol. 2005 May 1;95(9):1085-8
15842977
Mol Pharmacol. 2006 Oct;70(4):1340-9
16825483
J Biol Chem. 2003 Jun 13;278(24):21344-51
12672813
Circulation. 2008 Dec 9;118(24):2506-14
19029466
Circ Res. 2010 Jul 23;107(2):217-27
20508181
Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):2022-9
17615385
Acad Radiol. 2002 Jun;9(6):654-61
12061739
Circ Res. 2005 Sep 30;97(7):682-9
16141411
J Lipid Res. 2004 Jun;45(6):993-1007
15060092
Arterioscler Thromb Vasc Biol. 1999 May;19(5):1257-62
10323777
Bioorg Med Chem Lett. 2009 Jan 1;19(1):27-30
19058966
Am Heart J. 2009 Oct;158(4):513-519.e3
19781408
N Engl J Med. 2007 Apr 12;356(15):1503-16
17387127
Circulation. 2004 Sep 21;110(12):1701-5
15353488
J Am Coll Cardiol. 2009 Mar 17;53(11):962-71
19281927
J Am Coll Cardiol. 2008 Mar 18;51(11):1098-103
18342229
Lab Invest. 1989 Mar;60(3):455-61
2927083
Arch Biochem Biophys. 1955 Feb;54(2):558-9
14350806
Biochem Pharmacol. 2009 Apr 15;77(8):1316-27
19101522
Am J Cardiol. 2007 Dec 3;100(11 A):n15-9
18047847
JAMA. 2008 Jun 18;299(23):2777-88
18560005
J Lipid Res. 2008 Jun;49(6):1344-52
18323573
N Engl J Med. 2001 Nov 29;345(22):1583-92
11757504
J Clin Lipidol. 2010 Sep-Oct;4(5):399-404
21122683
Genes Dev. 2000 Nov 15;14(22):2819-30
11090130
Circulation. 2003 Aug 12;108(6):661-3
12900335
Arterioscler Thromb Vasc Biol. 1997 Jun;17(6):1053-9
9194754
J Clin Endocrinol Metab. 2006 Sep;91(9):3382-8
16684835
Atherosclerosis. 2010 Aug;211(2):558-64
20466371
J Am Coll Cardiol. 2010 Jun 15;55(24):2727-35
20538165
J Biol Chem. 2003 Mar 14;278(11):9869-74
12522134
J Lipid Res. 2008 Nov;49(11):2302-11
18621920
Am Heart J. 2000 Jun;139(6):993-9
10827379
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11448-53
8876155
JAMA. 2003 Nov 5;290(17):2292-300
14600188
Eur Heart J. 2010 Feb;31(4):480-8
20097702
Mol Cell Biol. 2001 May;21(9):2991-3000
11287605
Circ Res. 2008 Nov 7;103(10):1084-91
18832751
Circulation. 2009 Jul 14;120(2):160-9
19564558
J Lipid Res. 2001 Jul;42(7):1096-104
11441137
J Biol Chem. 2000 Sep 8;275(36):28240-5
10858438
J Cardiovasc Pharmacol. 2005 Jun;45(6):591-8
15897787
J Biol Chem. 2007 Jun 22;282(25):18028-18036
17452318
Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1430-8
20448206
Atherosclerosis. 2005 Dec;183(2):222-9
16285990
Circulation. 1998 Mar 3;97(8):780-5
9498542
Circulation. 2009 Aug 18;120(7):549-52
19652089
Circ Res. 2002 May 17;90(9):974-80
12016263
J Clin Invest. 2007 Aug;117(8):2337-46
17657314
J Clin Invest. 2001 Mar;107(5):565-73
11238557
J Lipid Res. 2007 Jun;48(6):1263-72
17325387
Br J Pharmacol. 2008 Aug;154(7):1465-73
18536749
Circulation. 2001 Apr 17;103(15):1949-54
11306522
Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1496-501
19661486
J Lipid Res. 2010 Jun;51(6):1496-503
20075422
Curr Atheroscler Rep. 2009 Jan;11(1):52-7
19080728
Tohoku J Exp Med. 2010 Mar;220(3):223-8
20208418
Arterioscler Thromb Vasc Biol. 2005 Jul;25(7):1426-32
15845909
Biochem Pharmacol. 2006 Feb 14;71(4):453-63
16325781
J Am Coll Cardiol. 1986 Dec;8(6):1245-55
3782631
Circulation. 2009 Nov 24;120(21):2095-104
19901191
Vox Sang. 1996;71(3):155-64
8912458
Am Heart J. 2009 Feb;157(2):352-360.e2
19185645
J Clin Invest. 2009 Apr;119(4):1042-50
19287092
J Biochem. 1994 Aug;116(2):257-62
7822240