Ang II Enhances Noradrenaline Release from Sympathetic Nerve Endings Thus Contributing to the Up-Regulation of Metalloprotease-2 in Aortic Dissection Patients' Aorta Wall

Zhipeng Hu,Zhiwei Wang,Zhimin Yang,Xiaoping Hu,Wanli Jiang,Hongbing Wu,Luocheng Li,Michael Bader

doi:10.1371/journal.pone.0076922

Zhipeng Hu, Zhiwei Wang + Show 6 more

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https://doi.org/10.1371/journal.pone.0076922

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Abstract

ObjectTo test the hypothesis that angiotensin II (Ang II) could enhance noradrenaline (NA) release from sympathetic nerve endings of the aorta thus contributing to the up-regulation of matrix metalloproteinase 2 (MMP-2) during the formation of aortic dissection (AD).MethodsAng II, NA, MMP-2, MMP-9 of the aorta sample obtained during operation from aortic dissection patients were detected by High Performance Liquid Chromatography and ELISA and compared with controls. Isotope labelling method was used to test the impact of exogenous Ang II and noradrenaline on the NA release and MMP-2, MMP-9 expression on Sprague Dawley (SD) rat aorta rings in vitro. Two kidneys, one clip, models were replicated for further check of that impact in SD rats in vivo.ResultsThe concentration of Ang II, MMP-2, 9 was increased and NA concentration was decreased in aorta samples from AD patients. Exogenous Ang II enhanced while exogenous NA restrained NA release from aortic sympathetic endings. The Ang II stimulated NA release and the following MMP-2 up-regulation could be weakened by Losartan and chemical sympathectomy. Beta blocker did not influence NA release but down-regulated MMP-2. Long term in vivo experiments confirmed that Ang II could enhance NA release and up-regulate MMP-2.ConclusionsAD is initiated by MMP-2 overexpression as a result of increased NA release from sympathetic nervous endings in response to Ang II. This indicates an interaction of RAS and SAS during the formation of AD.

Highlights

Both renin–angiotensin system (RAS)and sympathetic adrenergic system(SAS)participate in the pathological process of aortic dissection (AD)
matrix metalloproteinase 2 (MMP-2) and Matrix metalloproteinase 9 (MMP-9) in the aorta samples were determined by ELISA
High Performance Liquid Chromatography was used for detecting tissue angiotensin II (Ang II) and NA concentration in aorta samples

Summary

Introduction

Both renin–angiotensin system (RAS)and sympathetic adrenergic system(SAS)participate in the pathological process of aortic dissection (AD). The two most widely used AD animal models are based on subcutaneous injection of angiotensin II (Ang II) combined with apolipoprotein-E (ApoE) knock-out or betaaminopropionitrile monofumarate (BAPN) pretreatment [1,2]. Adrenergic antagonists such as b-blockers were widely used for preventing AD and have shown the nice effect [6,7]. Their rationale includes reduction in arterial pressure and heart rate leading to decreased shear stress on the aorta and slower aortic root growth [8]

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