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

• DOI: 10.1111/bph.70006
• Publication Date: 2025-02-19T00:03:47Z
• Authors: Xiaohui Zeng; Zhuoji Ma; Shanshan Wen; Liang Zhou; Wanxian Hong; Zhixiong Wu; Chunxian Cen; Qianwen Bai; Shangwei Ding; Xin Chen; Jian Wang; Lingdan Chen; Wenju Lu; Tao Wang

AbstractBackground and PurposeRight ventricular (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. Imatinib has been reported to be cardiotoxic in the left heart. We hypothesise that imatinib damages the pressure overloaded RV via its direct effects within the heart, which may counteract its therapeutic effects in haemodynamic improvement of PH.Experimental ApproachA pulmonary arterial banding (PAB) rat model with fixed pulmonary artery narrowing was performed to avoid changes in RV afterload.Key ResultsIn PAB rats, imatinib treatment decreased the survival rate and exacerbated RV dysfunction, myocardial hypertrophy, apoptosis and fibrosis. In vitro, imatinib increased cardiomyocyte hypertrophy and did not change cardiac fibroblasts activation; however, imatinib‐treated conditioned medium from cardiomyocytes promoted fibroblast activation. Mechanistically, imatinib increased the phosphorylation of c‐jun N‐terminal kinase (JNK) and the expression of RUNX family transcription factor 2 (Runx2), and subsequently promoted the transcription of thrombospondin 4 (THBS4) and connective tissue growth factor (CTGF) in RV cardiomyocytes. Finally, SP600125, a JNK inhibitor, significantly alleviated imatinib‐induced RV failure in PAB rats and enhanced the effects of imatinib on RV function improvement in SU5416 + hypoxia‐induced PH rats without affecting pulmonary artery narrowing.Conclusion and ImplicationsWe demonstrate for the first time that 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.