Rho kinase inhibition ameliorates vascular remodeling and blood pressure elevations in a rat model of apatinib-induced hypertension

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 dosedependently. 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.

Research on the Mechanism and Prevention of Hypertension Caused by Apatinib Through the RhoA/ROCK Signaling Pathway in a Mouse Model of Gastric Cancer

“…Accumulating evidence strongly suggests that ROCK is dominantly involved in the regulation of vascular contraction, and Y27632 most likely targets ROCK and normalizes contractile dysfunction ( 54 ). Therefore, Y27632 may counteract the BP-increasing effects of VEGF antagonists and promote their antineoplastic effects ( 3 ). We confirmed that the tumor volume decreased after Y27632 intervention, which means that Y27632 does not affect the antitumor efficacy of apatinib in the treatment of gastric cancer and is the best choice for the treatment of TKI-induced hypertension.…”

“…ROCK, a serine/threonine kinase and an important downstream effector of the small G protein RhoA, is an important factor in the development of smooth muscle tone ( 59 ). We previously demonstrated that apatinib increases BP in a rat model by activating the RhoA/ROCK signaling pathway and that this increase is reversed by Y27632 ( 3 ). On this basis, we carried out experiment to further simulate the real tumor environment.…”

“…Hypertension is one of the most common adverse events caused by antiangiogenic antitumor drugs. Increased blood pressure (BP) not only causes discontinuation of antitumor therapy but also exacerbates the occurrence of cardiovascular events ( 3 ). A phase III clinical trial has proven that apatinib is safe and effective in patients with advanced gastric cancer ( 4 ).…”

Rho kinase inhibition: from hypertension to cardiovascular–renal remodeling and more

“…We feel that our extensive studies in patients with Gitelmans's and Bartter's syndrome (GS/BS) and in hypertensive patients may indirectly provide further mechanistic support coming from studies in humans for the contention of Li et al [3] regarding the role of ROCK activation and the antihypertensive and antiremodeling effects of ROCK inhibition derived by their study in an animal model.…”

“…Recently, Li et al [3] in a recent article published in the Journal of Hypertension have added another piece of knowledge regarding the likely beneficial effect, during antitumoral therapy, of ROCK inhibition for hypertension and cardiovascular remodeling induced by tyrosin kinase inhibitors (TKIs) targeting endothelial growth factors. Exploring the role of RhoA/ROCK signaling pathway in a rat model of apatinibinduced hypertension, Li et al [3] have, in fact, provided evidence suggesting that the activation of the RhoA/ROCK signaling pathway could be the underlying mechanism of apatinib-induced hypertension and induction of vascular remodeling in terms of increased aortic media thickness/ lumen diameter ratio and collagen content of aortic media, whereas ROCK inhibition promoted in this animal model both attenuation of hypertension and vascular remodeling; therefore, supporting a potential therapeutic value for ROCK inhibition in the treatment of hypertension and vascular remodeling-induced by apatinib, a selective TKI, approved in China for the treatment of gastric metastatic cancer [3].…”