Effects of 6-mercaptopurine in pressure overload induced right heart failure

Julie Birkmose Axelsen, Stine Andersen, Xiao-Qing Sun, Steffen Ringgaard, Janus Adler Hyldebrandt, Kondababu Kurakula, Marie-José Goumans, Frances S. de Man, Jens Erik Nielsen-Kudsk, Harm-Jan Bogaard, Asger Andersen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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-mercapto-purine (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.
Original languageEnglish
Article numbere0225122
JournalPLoS ONE
Volume14
Issue number11
DOIs
Publication statusPublished - 2019

Cite this

Axelsen, J. B., Andersen, S., Sun, X-Q., Ringgaard, S., Hyldebrandt, J. A., Kurakula, K., ... Andersen, A. (2019). Effects of 6-mercaptopurine in pressure overload induced right heart failure. PLoS ONE, 14(11), [e0225122]. https://doi.org/10.1371/journal.pone.0225122
Axelsen, Julie Birkmose ; Andersen, Stine ; Sun, Xiao-Qing ; Ringgaard, Steffen ; Hyldebrandt, Janus Adler ; Kurakula, Kondababu ; Goumans, Marie-José ; de Man, Frances S. ; Nielsen-Kudsk, Jens Erik ; Bogaard, Harm-Jan ; Andersen, Asger. / Effects of 6-mercaptopurine in pressure overload induced right heart failure. In: PLoS ONE. 2019 ; Vol. 14, No. 11.
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title = "Effects of 6-mercaptopurine in pressure overload induced right heart failure",
abstract = "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-mercapto-purine (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.",
author = "Axelsen, {Julie Birkmose} and Stine Andersen and Xiao-Qing Sun and Steffen Ringgaard and Hyldebrandt, {Janus Adler} and Kondababu Kurakula and Marie-Jos{\'e} Goumans and {de Man}, {Frances S.} and Nielsen-Kudsk, {Jens Erik} and Harm-Jan Bogaard and Asger Andersen",
year = "2019",
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language = "English",
volume = "14",
journal = "PLoS ONE",
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Axelsen, JB, Andersen, S, Sun, X-Q, Ringgaard, S, Hyldebrandt, JA, Kurakula, K, Goumans, M-J, de Man, FS, Nielsen-Kudsk, JE, Bogaard, H-J & Andersen, A 2019, 'Effects of 6-mercaptopurine in pressure overload induced right heart failure' PLoS ONE, vol. 14, no. 11, e0225122. https://doi.org/10.1371/journal.pone.0225122

Effects of 6-mercaptopurine in pressure overload induced right heart failure. / Axelsen, Julie Birkmose; Andersen, Stine; Sun, Xiao-Qing; Ringgaard, Steffen; Hyldebrandt, Janus Adler; Kurakula, Kondababu; Goumans, Marie-José; de Man, Frances S.; Nielsen-Kudsk, Jens Erik; Bogaard, Harm-Jan; Andersen, Asger.

In: PLoS ONE, Vol. 14, No. 11, e0225122, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Effects of 6-mercaptopurine in pressure overload induced right heart failure

AU - Axelsen, Julie Birkmose

AU - Andersen, Stine

AU - Sun, Xiao-Qing

AU - Ringgaard, Steffen

AU - Hyldebrandt, Janus Adler

AU - Kurakula, Kondababu

AU - Goumans, Marie-José

AU - de Man, Frances S.

AU - Nielsen-Kudsk, Jens Erik

AU - Bogaard, Harm-Jan

AU - Andersen, Asger

PY - 2019

Y1 - 2019

N2 - 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-mercapto-purine (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.

AB - 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-mercapto-purine (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.

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DO - 10.1371/journal.pone.0225122

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Axelsen JB, Andersen S, Sun X-Q, Ringgaard S, Hyldebrandt JA, Kurakula K et al. Effects of 6-mercaptopurine in pressure overload induced right heart failure. PLoS ONE. 2019;14(11). e0225122. https://doi.org/10.1371/journal.pone.0225122