title: Human resistin in chemotherapy-induced heart failure in humanized male mice and in women treated for breast cancer.
abstract: Resistin is a circulating mediator of insulin resistance mainly expressed in human monocytes and responsive to inflammatory stimuli. Recent clinical studies have connected elevated resistin levels with the development and severity of heart failure. To further our understanding of the role of human resistin in heart failure, we studied a humanized mouse model lacking murine resistin but transgenic for the human Retn gene (Hum-Retn mice), which exhibits basal and inflammation-stimulated resistin levels similar to humans. Specifically, we explored whether resistin underlies acute anthracycline-induced cardiotoxicity. Remarkably, doxorubicin (25mg/kg ip) led to a 4-fold induction of serum resistin levels in Hum-Retn mice. Moreover, doxorubicin-induced cardiotoxicity was greater in the Hum-Retn mice than in littermate controls not expressing human resistin (Retn(-/-)). Hum-Retn mice showed increased cardiac mRNA levels of inflammatory and cell adhesion genes compared with Retn(-/-) mice. Macrophages, but not cardiomyocytes, from Hum-Retn mice treated with doxorubicin in vitro showed dramatic induction of hRetn (human resistin) mRNA and protein expression. We also examined resistin levels in anthracycline-treated breast cancer patients with and without cardiotoxicity. Intriguingly, serum resistin levels in women undergoing anthracycline-containing chemotherapy increased significantly at 3 months and remained elevated at 6 months in those with subsequent cardiotoxicity. Further, elevation in resistin correlated with decline in ejection fraction in these women. These results suggest that elevated resistin is a biomarker of anthracycline-induced cardiotoxicity and may contribute in the development of heart failure via its direct effects on macrophages. These results further implicate resistin as a link between inflammation, metabolism, and heart disease.
authors: MD, PhD, 3400 Civic Center Blvd, Smilow Center for Translational Research, 12-102, Philadelphia, PA 19104. lazar@mail.med.upenn.edu.
authors: Daniel R
authors: DR
authors: Schwartz
authors: Erika R
authors: ER
authors: Briggs
authors: Mohammed
authors: M
authors: Qatanani
authors: Heloisa
authors: H
authors: Sawaya
authors: Igal A
authors: IA
authors: Sebag
authors: Michael H
authors: MH
authors: Picard
authors: Marielle
authors: M
authors: Scherrer-Crosbie
authors: Mitchell A
authors: MA
authors: Lazar
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002478:Cells, Cultured; D004317:Doxorubicin / Q000009:adverse effects*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000139:chemically induced*; D006801:Humans; D017737:Macrophages, Peritoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D052243:Resistin / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D052243:Resistin; D004317:Doxorubicin; D000068878:Trastuzumab
references: Eur J Clin Invest. 2012 Oct;42(10):1079-86
references: 22712474
references: Oncologist. 2009 Jan;14(1):1-11
references: 19147689
references: Hum Exp Toxicol. 2007 Jan;26(1):19-35
references: 17334177
references: BMC Pharmacol. 2003 Dec 20;3:16
references: 14687418
references: Cardiovasc Ultrasound. 2013 May 01;11:12
references: 23634975
references: FEBS Lett. 2002 Oct 23;530(1-3):158-62
references: 12387885
references: J Mol Cell Cardiol. 1996 Sep;28(9):1931-43
references: 8899552
references: Mol Cancer Ther. 2011 Dec;10(12):2320-9
references: 21926192
references: J Card Fail. 2011 Jan;17(1):24-30
references: 21187261
references: J Mol Cell Cardiol. 2011 Aug;51(2):144-55
references: 21549710
references: Cardiovasc Toxicol. 2007;7(2):135-9
references: 17652818
references: Trends Endocrinol Metab. 2011 Jul;22(7):259-65
references: 21497511
references: J Mol Cell Cardiol. 2011 Sep;51(3):318-28
references: 21624372
references: Mol Cell Biol. 2010 May;30(9):2078-89
references: 20176806
references: J Am Coll Cardiol. 2011 Jan 4;57(1):99-109
references: 21185508
references: Clin Biochem. 2013 May;46(7-8):584-90
references: 23321342
references: Eur J Heart Fail. 2011 Nov;13(11):1161-71
references: 21952932
references: Circ J. 2007 Apr;71(4):460-4
references: 17384443
references: Toxicol Pathol. 2006;34(1):94-104
references: 16507550
references: Circulation. 2003 Feb 18;107(6):896-904
references: 12591762
references: J Pharmacol Exp Ther. 1999 Mar;288(3):938-44
references: 10027829
references: J Cell Mol Med. 2010 Jun;14(6B):1419-31
references: 19754671
references: Diabetes. 2011 Mar;60(3):775-83
references: 21282361
references: PLoS Med. 2004 Nov;1(2):e45
references: 15578112
references: Clin Biochem. 2009 Sep;42(13-14):1407-12
references: 19560452
references: Arterioscler Thromb Vasc Biol. 2009 Jul;29(7):1144-9
references: 19372460
references: Pharmacol Res. 2001 Mar;43(3):211-8
references: 11401411
references: J Card Fail. 2011 Dec;17(12):1004-11
references: 22123363
references: Am J Cardiol. 2011 May 1;107(9):1375-80
references: 21371685
references: Toxicol Pathol. 1993;21(4):362-8
references: 8290867
references: Cancer Chemother Pharmacol. 1990;26(1):9-12
references: 2322993
references: J Korean Med Sci. 2007 Feb;22(1):117-21
references: 17297263
references: Eur J Heart Fail. 2013 Dec;15(12):1350-62
references: 23845797
references: Fundam Clin Pharmacol. 2012 Jun;26(3):356-62
references: 21352350
references: Biochem Biophys Res Commun. 2003 Jan 10;300(2):472-6
references: 12504108
references: Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2305-12
references: 17573461
references: J Am Coll Cardiol. 2009 Mar 3;53(9):754-62
references: 19245965
references: Am J Cardiol. 2012 Dec 1;110(11):1679-86
references: 22917553
references: J Cardiovasc Med (Hagerstown). 2013 Feb;14(2):150-7
references: 22240747
references: Eur J Heart Fail. 2008 Mar;10(3):233-43
references: 18321777
references: Cardiovasc Res. 2006 Jan;69(1):76-85
references: 16271710
references: N Engl J Med. 1998 Sep 24;339(13):900-5
references: 9744975
references: Biochem Biophys Res Commun. 2003 Sep 19;309(2):286-90
references: 12951047
references: Cancer Res. 1993 Apr 1;53(7):1565-70
references: 8453624
references: Eur J Heart Fail. 2007 Aug;9(8):762-9
references: 17481944
references: Circulation. 2003 Aug 12;108(6):736-40
references: 12874180
references: BMC Cancer. 2013 Feb 04;13:54
references: 23374911
references: Nat Rev Cardiol. 2010 Oct;7(10):564-75
references: 20842180
references: Cell Tissue Res. 2013 Jan;351(1):161-74
references: 23086480
references: Eur J Heart Fail. 2012 Nov;14(11):1265-75
references: 22764185
references: J Biol Chem. 2005 Sep 9;280(36):31679-85
references: 15983036
references: J Clin Invest. 2009 Mar;119(3):531-9
references: 19188682
references: Am J Physiol Heart Circ Physiol. 2008 Jun;294(6):H2480-8
references: 18390820
references: Gynecol Oncol. 2012 Jun;125(3):742-50
references: 22370603
references: Circulation. 2006 May 9;113(18):2211-20
references: 16651473
references: Am J Pathol. 2010 Feb;176(2):687-98
references: 20035047
references: J Mol Cell Cardiol. 2008 Aug;45(2):270-80
references: 18597775
references: Cardiovasc Res. 2010 Sep 1;87(4):656-64
references: 20495188
references: J Clin Invest. 1981 Oct;68(4):1053-64
references: 7287901
references: Diabetes. 2001 Oct;50(10):2199-202
references: 11574398
references: Nature. 2001 Jan 18;409(6818):307-12
references: 11201732