Rho kinase inhibition ameliorates vascular remodeling and blood pressure elevations in a rat model of apatinib-induced hypertension. Issue 4 (2nd April 2022)

• Record Type: Journal Article
• Authors: Li, Caie; Ma, Liping; Wang, Qiongying; Shao, Xuejiao; Guo, Lu; Chen, Jianshu; Wang, Wenjuan; Yu, Jing
• Is Part Of: Journal of hypertension. Volume 40:Issue 4(2022)
• Page Start: 675
• Page End: 684
• Publication Date: 2022-04-02
• Subjects: apatinib -- hypertension -- RhoA/Rho-associated coiled-coil domain-containing protein kinase signaling pathway -- tyrosine kinase inhibitors -- vascular endothelial growth factor; Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/HJH.0000000000003060
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Objectives: Hypertension is one of the major adverse effects of tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors. However, the mechanism underlying TKIs-induced hypertension remains unclear. Here, we explored the role of the RhoA/Rho kinase (ROCK) signaling pathway in elevation of blood pressure (BP) induced by apatinib, a selective TKI approved in China for treatment of advanced or metastatic gastric cancer. A nonspecific ROCK inhibitor, Y27632, was then combined with apatinib and its efficacy in alleviating apatinib-induced hypertension was evaluated. Methods: Normotensive female Wistar–Kyoto rats were exposed to two different doses of apatinib, or apatinib combined with Y27632, or vehicle for 2 weeks. BP was monitored by a tail-cuff plethysmography system. The mRNA levels and protein expression in the RhoA/ROCK pathway were determined, and vascular remodeling assessed. Results: Administration of either a high or low dose of apatinib was associated with a rapid rise in BP, reaching a plateau after 12 days. Apatinib treatment mediated upregulation of RhoA and ROCK II in the mid-aorta, more significant in the high-dose group. However, ROCK I expression showed no statistically significant differences. Furthermore, the mRNA level of GRAF3 decreased dose-dependently. Apatinib administration was also associated with decreased levels of MLCP, and elevated endothelin-1 (ET-1) and collagen I, which were accompanied with increased mid-aortic media. However, treatment with Y27632 attenuated the above changes. Conclusion: These findings suggest that activation of the RhoA/ROCK signaling pathway could be the underlying mechanism of apatinib-induced hypertension, while ROCK inhibitor have potential therapeutic value.