15, 16-dihydrotanshinone I mitigates right ventricular hypertrophy in pulmonary arterial hypertension by suppressing HIF1A/CXCR4 signaling

Pathological progress of right ventricular hypertrophy contributes to the mortality of patients with pulmonary arterial hypertension (PAH), but the intervention strategy remains limited. 15,16-Dihydrotanshinone I (DHTS) has been implicated in the treatment of various cardiovascular diseases, but the effect of DHTS on PAH remains unclear. This study aimed to address the potential therapeutic targets and molecular mechanisms of DHTS for treating PAH. Network pharmacology was applied to analyze the target candidates for DHTS treatment against PAH. H9c2 cells were used to validate the effect of DHTS in vitro, while hypoxia-treated rats were used as a PAH model in vivo. A total of 15 genes were identified as hub genes of PAH, among which HIF1A/CXCR4 axis was identified as the core target for DHTS treatment. In vitro experiments demonstrated that DHTS dose- and time-dependently mitigated hypoxia-induced cytotoxicity in H9c2 cardiomyocytes, concomitant with down-regulation of HIF1A/CXCR4 signaling. Mechanistically, the protective effect of DHTS was associated with suppression of hypoxia-induced ferroptosis. The rescue experiments demonstrated that ectopic over expression of CXCR4 substantially abolished the effect of DHTS, suggesting that DHTS could mitigate hypoxia-induced cytotoxicity by suppressing ferroptosis via CXCR4. Furthermore, the in vivo data suggested that DHTS significantly suppressed the expression of HIF1A/CXCR4 under hypoxia, thereby leading to improved symptoms of hypoxia-induced right ventricular hypertrophy, cardiac dysfunction, and myocardial fibrosis. DHTS could significantly mitigate PAH-induced right ventricular hypertrophy by suppressing HIF1A/CXCR4 signaling, which may provide new strategies to improve the life quality of PAH patients