Rutaecarpine prevents hypertensive cardiac hypertrophy involving the inhibition of Nox4‐ROS‐ADAM17 pathway

Si‐Yu Zeng,Li Yang,Hui‐Qin Lu,Ling Gao,Xu‐Ping Qin,Qiu‐Jiang Yan

doi:10.1111/jcmm.14308

Abstract

Rutaecarpine attenuates hypertensive cardiac hypertrophy in the rats with abdominal artery constriction (AAC); however, its mechanism of action remains largely unknown. Our previous study indicated that NADPH oxidase 4 (Nox4) promotes angiotensin II (Ang II)‐induced cardiac hypertrophy through the pathway between reactive oxygen species (ROS) and a disintegrin and metalloproteinase‐17 (ADAM17) in primary cardiomyocytes. This research aimed to determine whether the Nox4‐ROS‐ADAM17 pathway is involved in the protective action of rutaecarpine against hypertensive cardiac hypertrophy. AAC‐induced hypertensive rats were adopted to evaluate the role of rutaecarpine in hypertensive cardiac hypertrophy. Western blotting and real‐time PCR were used to detect gene expression. Rutaecarpine inhibited hypertensive cardiac hypertrophy in AAC‐induced hypertensive rats. These findings were confirmed by the results of in vitro experiments that rutaecarpine significantly inhibited Ang II‐induced cardiac hypertrophy in primary cardiomyocytes. Likewise, rutaecarpine significantly suppressed the Nox4‐ROS‐ADAM17 pathway and over‐activation of extracellular signal‐regulated kinase (ERK) 1/2 pathway in the left ventricle of AAC‐induced hypertensive rats and primary cardiomyocytes stimulated with Ang II. The inhibition of Nox4‐ROS‐ADAM17 pathway and over‐activation of ERK1/2 might be associated with the beneficial role of rutaecarpine in hypertensive cardiac hypertrophy, thus providing additional evidence for preventing hypertensive cardiac hypertrophy with rutaecarpine.

Highlights

Hypertension, named high blood pressure, causes enor‐ mous social and economic burden throughout the world
We discovered that rutaecarpine alleviated hyper‐ tensive cardiac hypertrophy in abdomi‐ nal artery constriction (AAC)‐induced hypertensive rats, that rutaecarpine suppressed angiotensin II (Ang II)‐induced cardiac hypertrophy and that rutaecarpine inhibited the NADPH oxidase 4 (Nox4)‐reactive oxygen species (ROS)‐a disintegrin and metalloproteinase‐17 (ADAM17) pathway and over‐active ERK1/2 pathway in hypertrophic cardiomyocytes
No significant change was observed in blood pressure in sponta‐ neously hypertensive rats and vascular ADAM17 deficient mice infused with Ang II (1 μg/kg/min) for 2 weeks[37,38] Shen et al[40] found that lacking ADAM17 in vascular smooth cells only caused a transient reduction in blood pressure during the first week of Ang II infusion (1.5 mg/kg/day)

Summary

Introduction

Hypertension, named high blood pressure, causes enor‐ mous social and economic burden throughout the world. High blood pressure induces pathological cardiac hypertrophy, usu‐ ally characterized by an enlarged cardiomyocyte, an increased protein synthesis and the reactivation of the foetal gene program. Ongoing high blood pressure promotes the tran‐ sition from adaptive hypertrophy to maladaptive hypertrophy, eventually leading to sudden death, malignant arrhythmia and heart failure.[1] pathological cardiac hypertrophy is an im‐ portant adverse sign for the cardiovascular events, and inhibiting. Rutaecarpine (8,13‐dihydroindolo‐(2′,3′:3,4)pyrido(2,1‐b) quinazolin‐5(7H)‐one) is extracted from the dried fruit of Evodia rutaecarpa (Juss) Benth, known as traditional Chinese herb Wu‐Zhu‐Yu used for antihypertensive therapy.[2] Rutaecarpine was shown to cause vasorelaxing in a concentration‐dependent manner in rat aortic rings, inhibit anaphylaxis‐induced vasoconstriction in guinea‐pigs, and diminish blood pressure in anaesthetized rats.[3,4]

Objectives

Conclusion