Imatinib aggravates pressure-overload-induced right ventricle failure via JNK/Runx2 pathway

Background: Right ventricle (RV) function is the key prognostic determinant of pulmonary hypertension (PH). In PH patients, imatinib treatment decreases pulmonary vascular resistance and improves exercise capacity, but does not change mortality or duration to clinical worsening. And imatinib have been reported to be cardiotoxic. Thus, we hypothesize that imatinib damages the pressure overloaded RV via its effects in the heart, which may counteract the therapeutic effects in hemodynamic improvement among PH. Methods: Surgical pulmonary artery banding (PAB) rat model with fixed pulmonary artery narrowing was performed to investigate the effects of imatinib within RV, in order to avoid the potential changes in the afterload. Primary cardiomyocytes were used to explore mechanisms in vitro. Results: In PAB rats, imatinib treatment decreased the survival rate (85.7% vs 46.2%), exacerbated RV dysfunction, increased right atrial pressure (4.808 ± 0.4756 mmHg vs 7.796 ± 0.7204 mmHg), and RV myocardial hypertrophy, fibrosis and apoptosis. Mechanistically, imatinib increased the phosphorylation of c-jun N-terminal kinase (JNK) and expression of RUNX family transcription factor 2 (Runx2), and subsequently promoted the transcription of thrombospondin 4 (THBS4) and connective tissue growth factor (CTGF) in cardiomyocytes. Finally, SP600125, an JNK inhibitor, significantly alleviated imatinib-induced RV failure in PAB rats, and enhanced the therapeutic effect of imatinib on RV function improvement in SU5416-hypoxia induced PH. Conclusions: Imatinib aggravates RV failure under pressure overload through JNK/Runx2 pathway, and JNK inhibition improves the therapeutic effects of imatinib on RV function in PH.