title: Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice.
abstract: Diabetes is a major health problem associated with adverse cardiovascular outcomes. The apolipoprotein A-I mimetic peptide L-4F is a putative anti-diabetic drug, has antioxidant and anti-inflammatory proprieties and improves endothelial function. In obese mice L-4F increases adiponectin levels, improving insulin sensitivity, and reducing visceral adiposity. We hypothesized that the pleiotropic actions of L-4F can prevent heart and coronary dysfunction in a mouse model of genetically induced Type II diabetes. We treated db/db mice with either L-4F or vehicle for 8 weeks. Trans-thoracic echocardiography was performed; thereafter, isolated hearts were subjected to ischemia/reperfusion (IR). Glucose, insulin, adiponectin, and pro-inflammatory cytokines (IL-1β, TNF-α, MCP-1) were measured in plasma and HO-1, pAMPK, peNOS, iNOS, adiponectin, and superoxide in cardiac tissue. In db/db mice L-4F decreased accumulation of subcutaneous and total fat, and increased insulin sensitivity and adiponectin levels while lowering inflammatory cytokines (P < 0.05). L-4F normalized in vivo left ventricular (LV) function of db/db mice, increasing (P < 0.05) fractional shortening and decreasing (P < 0.05) LV dimensions. In I/R experiments, L-4F prevented coronary microvascular resistance from increasing and LV function from deteriorating in the db/db mice. These changes were associated with increased cardiac expression of HO-1, pAMPK, peNOS, and adiponectin and decreased levels of superoxide and iNOS (P < 0.01). In the present study we showed that L-4F prevented myocardial and coronary functional abnormalities in db/db mice. These effects were associated with stimulation of HO-1 resulting in increased levels of anti-inflammatory, anti-oxidative, and vasodilatatory action through a mechanism involving increased levels of adiponectin, pAMPK, and peNOS.
authors: Scuola Superiore Sant'Anna, Pisa, Italy.
authors: C
authors: C
authors: Vecoli
authors: J
authors: J
authors: Cao
authors: D
authors: D
authors: Neglia
authors: K
authors: K
authors: Inoue
authors: K
authors: K
authors: Sodhi
authors: L
authors: L
authors: Vanella
authors: K K
authors: KK
authors: Gabrielson
authors: D
authors: D
authors: Bedja
authors: N
authors: N
authors: Paolocci
authors: A
authors: A
authors: L'abbate
authors: N G
authors: NG
authors: Abraham
references: Circ Res. 2003 Sep 19;93(6):507-14
references: 12933701
references: Curr Vasc Pharmacol. 2005 Jul;3(3):253-66
references: 16026322
references: J Lipid Res. 2008 Aug;49(8):1658-69
references: 18426778
references: Acta Diabetol. 1995 Dec;32(4):235-43
references: 8750762
references: Diabetes. 2002 Jun;51(6):1938-48
references: 12031984
references: Cardiovasc Drugs Ther. 2008 Apr;22(2):83-9
references: 18247111
references: J Lipid Res. 2008 Jun;49(6):1344-52
references: 18323573
references: J Lipid Res. 2008 Nov;49(11):2302-11
references: 18621920
references: Arterioscler Thromb Vasc Biol. 2000 Jun;20(6):1595-9
references: 10845877
references: Circulation. 2001 Jun 5;103(22):2668-73
references: 11390335
references: Am J Physiol Endocrinol Metab. 2008 Nov;295(5):E1269-76
references: 18796548
references: J Lipid Res. 2011 Feb;52(2):361-73
references: 21068008
references: Science. 2005 Jan 21;307(5708):373-5
references: 15662001
references: Circulation. 2005 Jun 14;111(23):3126-34
references: 15939814
references: J Lipid Res. 2009 Jul;50(7):1293-304
references: 19224872
references: Circulation. 2005 Nov 15;112(20):3066-72
references: 16275870
references: Circ Res. 2005 May 13;96(9):939-49
references: 15890981
references: Nat Clin Pract Cardiovasc Med. 2006 Oct;3(10):540-7
references: 16990839
references: J Cell Mol Med. 2011 Apr;15(4):763-72
references: 20193037
references: Nat Clin Pract Endocrinol Metab. 2007 Jan;3(1):46-56
references: 17179929
references: Circulation. 2010 May 4;121(17):1912-25
references: 20404253
references: Nature. 1999 Jun 10;399(6736):601-5
references: 10376603
references: Am J Physiol Heart Circ Physiol. 2005 Jan;288(1):H13-21
references: 15345489
references: FEBS Lett. 1999 Jan 29;443(3):285-9
references: 10025949
references: Cardiovasc Res. 2007 Jun 1;74(3):471-9
references: 17362898
references: J Am Coll Cardiol. 2010 Sep 28;56(14):1113-32
references: 20863953
references: Hypertension. 2009 Mar;53(3):508-15
references: 19171794
references: Diabetes. 2002 Apr;51(4):1076-82
references: 11916928
references: Arterioscler Thromb. 1992 Aug;12(8):886-94
references: 1637786
references: J Cell Biochem. 2010 Apr 1;109(5):1033-44
references: 20108250
references: Arterioscler Thromb Vasc Biol. 2010 Feb;30(2):164-8
references: 19608977
references: Cardiol Rev. 2010 May-Jun;18(3):141-7
references: 20395699
references: Circulation. 2007 Mar 20;115(11):1408-16
references: 17339545
references: J Pharmacol Exp Ther. 2007 Aug;322(2):514-20
references: 17488882
references: Diabetes Care. 1985 May-Jun;8(3):230-4
references: 4006657
references: Metabolism. 2011 Feb;60(2):227-33
references: 20199784
references: Circulation. 2001 Apr 24;103(16):2055-9
references: 11319194
references: J Clin Invest. 2006 Jul;116(7):1784-92
references: 16823476
references: Circulation. 2002 Jan 22;105(3):290-2
references: 11804981
references: Am J Physiol Heart Circ Physiol. 2007 Dec;293(6):H3532-41
references: 17906103
references: Circ Res. 2001 Feb 2;88(2):E14-22
references: 11157681
references: Curr Cardiol Rep. 2007 May;9(3):236-41
references: 17470337
references: J Clin Invest. 2005 May;115(5):1221-31
references: 15841206
references: Heart Fail Clin. 2006 Jan;2(1):13-23
references: 17386873
references: J Clin Invest. 2004 Aug;114(4):495-503
references: 15314686
references: Am J Physiol Heart Circ Physiol. 2005 Nov;289(5):H2144-52
references: 16006542
references: Curr Pharm Des. 2010 May;16(13):1504-16
references: 20196738
references: Clin Exp Pharmacol Physiol. 2003 Nov;30(11):867-78
references: 14678252
references: Curr Atheroscler Rep. 2009 Jan;11(1):52-7
references: 19080728
references: J Am Coll Cardiol. 2008 Jan 15;51(2):93-102
references: 18191731
references: Am J Physiol Heart Circ Physiol. 2002 Sep;283(3):H976-82
references: 12181126