Key result
Mitochondrial c-Src inhibition reduces OXPHOS, ROS, and fibrogenesis in RV fibroblasts from PH models.
Why the study?
RV fibrosis is an important prognostic marker in PH without targeted therapies, but little is known about metabolic alterations in RV CF.
Does inhibition of mitochondrial oxidative phosphorylation reduce pro-fibrotic pathways in right ventricular cardiac fibroblasts in preclinical models of pulmonary hypertension?
Does inhibition of mitochondrial oxidative phosphorylation reduce pro-fibrotic pathways in right ventricular cardiac fibroblasts in preclinical models of pulmonary hypertension?
Targeting mitochondrial oxidative phosphorylation via c-Src inhibition reduces pro-fibrotic pathways in right ventricular cardiac fibroblasts, suggesting a novel anti-fibrotic approach in pulmonary hypertension.
RV fibroblast metabolic shifts may offer antifibrotic targets in PH; leaves open clinical translation from this animal model.
Rationale Right ventricular (RV) fibrosis is an important prognostic marker in pulmonary hypertension (PH). Yet, no RV fibrosis targeted therapies are available. Cardiac fibroblasts (CF) critically contribute to myocardial fibrosis. Evidence suggests that metabolic changes in fibroblasts may play an important role in fibrotic conditions. However, little is known about the metabolic alterations in RV CF in PH. The objective of this study is to determine the metabolic features in RV CF using preclinical PH models and to investigate whether metabolic regulation can be used to mediate CF function. Methods SU5416-hypoxia (SuHx)-induced PH model (Sprague-Dawley and Fischer rats) and pulmonary artery banding model (Sprague-Dawley rats) were used. After Echocardiography and hemodynamic, RV tissues were collected for fibrosis analysis and single nuclei RNA sequencing (snRNAseq). RV CFs were isolated to assess mitochondrial function and glycolysis using Seahorse XF Pro Analyzer. CF from healthy rats were treated with TGF-β to assess the fibrotic stimulation-induced metabolic and functional changes. IM156 and mitochondrial targeted kinase dead (KD) c-Src were used to chemically or genetically inhibit mitochondrial oxidative phosphorylation (OXPHOS), respectively. Mitochondrial ROS was measured using MitoSox. Results PH and PAB models developed RV dysfunction, which were more severe in the PH Fischer rats. sn-RNAseq showed increased fibrogenesis, OXPHOS, glucose pathways, and TGF-β signalling in RV CF from all three models. Collagen and OXPHOS were increased in CF isolated from PH rats compared to control rats. TGF-β stimulation significantly increased both OXPHOS and glycolysis in CF, which is associated with increased collagen production and α-SMA expression. IM156 dramatically attenuated basal and TGF-β induced increases in OXPHOS yet increased mitochondrial ROS and TGF-β induced glycolysis in CF. IM156 did not affect TGF-β induced collagen production. Mitochondrial c-Src kinase activity, which promotes complex I activity, is increased in RV CF from PH rats. Mitochondrial c-Src inhibition reduced TGF-β induced OXPHOS, mitochondrial ROS, collagen production, and α-SMA expression, but did not alter glycolysis. Conclusions Our data suggest that targeting OXPHOS in RV CF may be a novel anti-fibrotic approach in RV in settings of PH. Both OXPHOS and glycolysis are significantly increased in RV CF in PH and mitochondrial KD c-Src is superior to IM156 in reducing pro-fibrotic pathways.
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Pantry et al. (2026) studied Pulmonary hypertension. IM156 and mitochondrial targeted kinase dead (KD) c-Src vs. Control rats was evaluated on Metabolic features and fibrotic markers in right ventricular cardiac fibroblasts. Mitochondrial c-Src inhibition reduced TGF-β induced OXPHOS, mitochondrial ROS, collagen production, and α-SMA expression in right ventricular cardiac fibroblasts from pulmonary hypertension models.
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