Effects of 6-mercaptopurine in pressure overload induced right heart failure.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2019
2019
Historique:
received:
19
07
2019
accepted:
29
10
2019
entrez:
13
11
2019
pubmed:
13
11
2019
medline:
24
3
2020
Statut:
epublish
Résumé
Several antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effects of 6-mercaptopurine in rats with isolated right heart failure caused by pulmonary trunk banding (PTB). Male Wistar rat weanlings (112±2 g) were randomized to sham operation (sham, n = 10) or PTB. The PTB animals were randomized to placebo (PTB-control, n = 10) and 6-mercaptopurine (7.5 mg/kg/day) groups with treatment start before the PTB procedure (PTB-prevention, n = 10) or two weeks after (PTB-reversal, n = 10). Right ventricular effects were evaluated by echocardiography, cardiac MRI, invasive pressure-volume measurements, and histological and molecular analyses. PTB increased right ventricular afterload and caused right ventricular hypertrophy and failure. 6-mercaptopurine did not improve right ventricular function nor reduce right ventricular remodelling in both prevention and reversal studies compared with placebo-treated rats. Treatment with 6-mercaptopurine did not have any beneficial or detrimental effects on right ventricular function or remodelling. Our data suggest that treatment of pulmonary arterial hypertension with 6-mercaptopurine is not harmful to the failing right ventricle.
Sections du résumé
BACKGROUND
Several antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effects of 6-mercaptopurine in rats with isolated right heart failure caused by pulmonary trunk banding (PTB).
METHODS
Male Wistar rat weanlings (112±2 g) were randomized to sham operation (sham, n = 10) or PTB. The PTB animals were randomized to placebo (PTB-control, n = 10) and 6-mercaptopurine (7.5 mg/kg/day) groups with treatment start before the PTB procedure (PTB-prevention, n = 10) or two weeks after (PTB-reversal, n = 10). Right ventricular effects were evaluated by echocardiography, cardiac MRI, invasive pressure-volume measurements, and histological and molecular analyses.
RESULTS
PTB increased right ventricular afterload and caused right ventricular hypertrophy and failure. 6-mercaptopurine did not improve right ventricular function nor reduce right ventricular remodelling in both prevention and reversal studies compared with placebo-treated rats.
CONCLUSION
Treatment with 6-mercaptopurine did not have any beneficial or detrimental effects on right ventricular function or remodelling. Our data suggest that treatment of pulmonary arterial hypertension with 6-mercaptopurine is not harmful to the failing right ventricle.
Identifiants
pubmed: 31714926
doi: 10.1371/journal.pone.0225122
pii: PONE-D-19-19535
pmc: PMC6850541
doi:
Substances chimiques
Mercaptopurine
E7WED276I5
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0225122Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Cardiovasc Res. 2003 Sep 1;59(3):658-67
pubmed: 14499867
Cardiovasc Res. 2016 May 1;110(1):30-9
pubmed: 26790474
PLoS One. 2014 Apr 14;9(4):e94732
pubmed: 24733352
Chest. 2009 Mar;135(3):794-804
pubmed: 19265089
J Pharmacol Sci. 2009 Oct;111(2):193-200
pubmed: 19809219
Oncogene. 2007 May 31;26(26):3823-34
pubmed: 17146432
Chest. 2012 Aug;142(2):448-456
pubmed: 22281797
Mod Pathol. 2006 Jun;19(6):755-65
pubmed: 16575400
Eur Respir J. 2007 Jul;30(1):104-9
pubmed: 17360728
J Immunol. 2014 May 1;192(9):4370-8
pubmed: 24670805
J Biol Chem. 2018 Sep 7;293(36):14001-14011
pubmed: 30006349
Cardiovasc Res. 2019 Jun 1;115(7):1217-1227
pubmed: 30850841
Matrix Biol. 1998 Feb;16(7):387-98
pubmed: 9524359
Cardiovasc Res. 2017 Oct 1;113(12):1441-1452
pubmed: 28957536
Chest. 2015 Apr;147(4):1063-1071
pubmed: 25376008
Circ Heart Fail. 2016 Jul;9(7):
pubmed: 27370069
Chest. 2011 Jun;139(6):1285-1293
pubmed: 21071530
Circulation. 2007 Jan 30;115(4):493-500
pubmed: 17242285
J Neuroinflammation. 2016 Apr 13;13(1):78
pubmed: 27075886
Circulation. 2010 Aug 31;122(9):920-7
pubmed: 20713898
Eur Respir J. 2010 May;35(5):1079-87
pubmed: 20032020
Circulation. 2001 Jul 3;104(1):39-45
pubmed: 11435335
J Ultrasound Med. 2010 Dec;29(12):1771-8
pubmed: 21098849
Am J Respir Crit Care Med. 2006 May 1;173(9):1023-30
pubmed: 16456139
Patient Prefer Adherence. 2017 May 08;11:871-885
pubmed: 28507431
Eur Respir J. 2019 Sep 29;54(3):null
pubmed: 31273046
J Am Coll Cardiol. 2013 Dec 24;62(25 Suppl):D22-33
pubmed: 24355638
Mol Cell Biol. 2015 Oct;35(19):3312-23
pubmed: 26195821
Cardiol Young. 2016 Mar;26(3):451-8
pubmed: 25872028
J Clin Invest. 1997 Nov 1;100(9):2315-24
pubmed: 9410910
Eur J Clin Pharmacol. 1992;43(4):329-39
pubmed: 1451710
Cancer Chemother Pharmacol. 1999;43(2):133-40
pubmed: 9923818
Heart Fail Rev. 2015 Jul;20(4):475-91
pubmed: 25771982
Cardiovasc Res. 2015 Mar 1;105(3):260-70
pubmed: 25560320
Am J Physiol Heart Circ Physiol. 2018 Sep 1;315(3):H699-H708
pubmed: 29882684
Matrix Biol. 2018 Aug;68-69:507-521
pubmed: 29343458
Circulation. 2000 Aug 22;102(8):865-70
pubmed: 10952954
Acta Physiol (Oxf). 2009 Mar;195(3):321-38
pubmed: 19040711
Sci Rep. 2015 Oct 21;5:15404
pubmed: 26486271
J Mol Cell Cardiol. 2014 May;70:64-73
pubmed: 24492068
EMBO Mol Med. 2013 Jan;5(1):137-48
pubmed: 23197407
Gut. 1996 Sep;39(3):401-6
pubmed: 8949645
Am J Physiol Heart Circ Physiol. 2010 Jul;299(1):H1-9
pubmed: 20472764
Pediatr Cardiol. 1995 Mar-Apr;16(2):61-8
pubmed: 7784236
Eur Heart J. 2009 Aug;30(16):1995-2002
pubmed: 19556262
J Natl Cancer Inst. 2010 Jan 6;102(1):14-25
pubmed: 20007921
Circulation. 2009 Jul 7;120(1):42-9
pubmed: 19546388
Basic Res Cardiol. 2018 May 9;113(4):23
pubmed: 29744594
J Biol Chem. 2003 Jul 4;278(27):24776-90
pubmed: 12709428
Cardiovasc Res. 2016 May 15;110(2):188-99
pubmed: 26952044
Eur Heart J. 2011 Sep;32(17):2179-88
pubmed: 21228009
Trends Pharmacol Sci. 1997 Jan;18(1):3-7
pubmed: 9114722
J Pharmacol Exp Ther. 2017 Oct;363(1):20-34
pubmed: 28760737
Am J Physiol Heart Circ Physiol. 2016 Jul 1;311(1):H85-95
pubmed: 27199115
J Cardiovasc Med (Hagerstown). 2016 Aug;17(8):631-7
pubmed: 25003999
Adv Clin Exp Med. 2017 May-Jun;26(3):549-553
pubmed: 28791832
Eur Respir Rev. 2010 Mar;19(115):72-82
pubmed: 20956170
Circulation. 2010 Jul 13;122(2):156-63
pubmed: 20585011
Cardiovasc Res. 2013 Jul 1;99(1):111-20
pubmed: 23619422
J Biol Chem. 2003 Jul 4;278(27):24791-9
pubmed: 12709433
J Am Coll Cardiol. 2011 Dec 6;58(24):2511-9
pubmed: 22133851
J Vis Exp. 2018 Nov 29;(141):
pubmed: 30582605