Proteomic Analysis Permits the Identification of New Biomarkers of Arterial Wall Remodeling in Hypertension

Sandrine Delbosc,Liliane Louedec,Myriam Cubizolles,Mounsif Haloui,Eric T Fung,Morgan Dupuis,Vladimir N Podust,Olivier Meilhac,Jean-Baptiste Michel

doi:10.2119/2008-00030.delbosc

Sandrine Delbosc, Liliane Louedec + Show 7 more

Open Access

https://doi.org/10.2119/2008-00030.delbosc

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Abstract

Hypertension represents one of the main risk factors for vascular diseases. Genetic susceptibility may influence the rate of its development and the associated vascular remodeling. To explore markers of hypertension-related morbidity, we have used surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry to study changes in proteins released by the aorta of two rat strains with different susceptibilities to hypertension. Fischer and Brown Norway (BN) rats were divided into a control group and a group receiving low-dose N(Omega)-nitro-L-arginine methyl ester (L-NAME), a hypertensive drug, interfering with endothelial function. In spite of a significant elevation of blood pressure in both strains in response to L-NAME, BN rats exhibited a lower vascular remodeling in response to hypertension. Proteomic analysis of secreted aortic proteins by SELDI-TOF MS allowed detection of four mass-to-charge ratio (m/z) peaks whose corresponding proteins were identified as ubiquitin, smooth muscle (SM) 22alpha, thymosin beta4, and C-terminal fragment of filamin A, differentially secreted in Fischer rats in response to L-NAME. We have confirmed a strain-dependent difference in susceptibility to L-NAME-induced hypertension between BN and Fischer rats. The greater susceptibility of Fischer rats is associated with aortic wall hypertrophic remodeling, reflected by increased aortic secretion of four identified biomarkers. Similar variations in one of them, SM22alpha, also were observed in plasma, suggesting that this marker could be used to assess vascular damage induced by hypertension.

Highlights

Hypertension is a well-recognized risk factor for vascular diseases
Our results show that Brown Norway (BN) rats are less susceptible than Fischer rats to hypertension induced by the chronic blockade of nitric oxide (NO) production
The fact that BN rats are more resistant to L-NAME administration has been confirmed by a recent study which demonstrated that transfer of chromosome 1 from the BN rat to the Fawn-Hooded Hypertensive rat reduced the severity of L-NAME-induced hypertension and renal disease [8]

Summary

Introduction

Chronic blockade of nitric oxide (NO) production by administration of L-NAME is a well-established model of hypertension in rats, in which animals develop an intensive molecular and cellular response in the arterial wall leading to a significantly reduced survival rate [1,2]. To explore new potential markers of the arterial wall response to L-NAME-induced hypertension, we used SELDI-TOF mass spectrometry technology, a differential proteomic approach allowing assessment of the differences in abundance of various proteins between different experimental and biological conditions [3,4,5]. In a previous, unpublished study, we showed that survival rates of Brown Norway (BN) and Fischer rat strains differ significantly after L-NAME administration. We selected these two rat strains with different susceptibilities to L-NAME-induced hypertension for identifying new potential biomarkers of hypertension and endothelial dysfunction-induced arterial wall remodeling. We used the SELDI-TOF-MS approach to compare the profiles of proteins released from the arterial wall of hypertensive, compared with normotensive, rats

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