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


Autoři: Julie Birkmose Axelsen aff001;  Stine Andersen aff001;  Xiao-Qing Sun aff002;  Steffen Ringgaard aff003;  Janus Adler Hyldebrandt aff004;  Kondababu Kurakula aff005;  Marie-José Goumans aff005;  Frances S. de Man aff002;  Jens Erik Nielsen-Kudsk aff001;  Harm-Jan Bogaard aff002;  Asger Andersen aff001
Působiště autorů: Department of Cardiology–Research, Aarhus University Hospital, Aarhus, Denmark aff001;  Department of Pulmonology, VU University Medical Center, Amsterdam, The Netherlands aff002;  MR Centre, Aarhus University Hospital, Aarhus, Denmark aff003;  Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark aff004;  Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands aff005
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225122

Souhrn

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.

Klíčová slova:

Cardiac ventricles – Collagens – Fibrosis – Gene expression – Inflammation – Protein expression – Pulmonary hypertension – Surgical and invasive medical procedures


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