Unveiling the mechanism of BDKRB2-mediated protection against hypertension induced by apatinib: a time-series transcriptomic study

Background Hypertension is one of the major adverse effects of tyrosine kinase inhibitors(TKIs) targeting vascular endothelial growth factors-2(VEGFR-2).Here, we explored the role of the BDKRB2 in elevation of blood pressure (BP) induced by Apatinib(Apa),a novel targeted antiangiogenic molecule, could generate highly selective competition in the vascular endothelial growth factor receptor-2, involved in tumor progression and metastasis. It has been implied as a promising cancer treatment agent that can prevent tumor cell proliferation meanwhile inhibit tumor angiogenesis.Based on the comparable survival results, the molecular mechanisms of apatinib are prospective to include the antiangiogenic, apoptosis-inducing, and autophagy-inducing properties in the corresponding signaling pathway.However, the Transcriptome and critical signaling pathway underlying TKIs-induced hypertension remains unclear. Methods Male wild-type C57BL/6 mice (10 weeks old) were administered Apa (155 mg/kg/day) or saline by oral gavage for 1, 3, and 7 days. Tail-cuff blood pressure was monitored daily throughout a 14-day period.On day 15, mid-aortic tissue segments were harvested and subjected to time-series transcriptomic analysis using RNA sequencing (RNA-Seq).Serum concentrations of BDKRB2 were determined by ELISA in three groups of clinical patients: gastric cancer patients treated with apatinib, gastric cancer patients not treated with apatinib, and non-neoplastic patients without apatinib administration. Results We identified 2513 differentially expressed genes (DEGs) from the aortic tissue samples.These DEGs were predominantly enriched in biological processes including aerobic respiration, mitochondrial redox homeostasis, and the tricarboxylic acid (TCA) cycle in aortic endothelial cells following Apa treatment.Moreover, co-expression network analysis revealed that Bradykinin Receptor B2 (BDKRB2) exhibited high degree and betweenness centrality, indicating its pivotal role in mitochondrial redox processes.The expression of BDKRB2 was significantly down-regulated at various time points in aortic tissues following Apatinib treatment.Overexpression of BDKRB2 in aortic endothelial cells was associated with a significant reduction in hypertension susceptibility and aortic inflammation in mice.These beneficial effects were associated with enhanced ATP production, increased expression of mitochondrial oxidative phosphorylation system complexes I-V, and upregulation of endothelial nitric oxide synthase (eNOS). Conclusion Our study delineated the dynamic changes of differentially expressed genes (DEGs) involved in Apa-induced hypertension.And we identified that BDKRB2 plays a protective role in the regulation of hypertension development，its upregulation may represent a potential therapeutic option for the treatment of Apa-induced cardiotoxicity and drug refinement.