Identification of Aortic Proteins Involved in Arterial Stiffness in Spontaneously Hypertensive Rats Treated With Perindopril:A Proteomic Approach.

Danyelle S Miotto,Aline Dionizio,Anderson S Zago,Marília Afonso Rabelo Buzalaf,Sandra L Amaral,André M Jacomini

doi:10.3389/fphys.2021.624515

Abstract

Arterial stiffness, frequently associated with hypertension, is associated with disorganization of the vascular wall and has been recognized as an independent predictor of all-cause mortality. The identification of the molecular mechanisms involved in aortic stiffness would be an emerging target for hypertension therapeutic intervention. This study evaluated the effects of perindopril on pulse wave velocity (PWV) and on the differentially expressed proteins in aorta of spontaneously hypertensive rats (SHR), using a proteomic approach. SHR and Wistar rats were treated with perindopril (SHRP) or water (SHRc and Wistar rats) for 8 weeks. At the end, SHRC presented higher systolic blood pressure (SBP, +70%) and PWV (+31%) compared with Wistar rats. SHRP had higher values of nitrite concentration and lower PWV compared with SHRC. From 21 upregulated proteins in the aortic wall from SHRC, most of them were involved with the actin cytoskeleton organization, like Tropomyosin and Cofilin-1. After perindopril treatment, there was an upregulation of the GDP dissociation inhibitors (GDIs), which normally inhibits the RhoA/Rho-kinase/cofilin-1 pathway and may contribute to decreased arterial stiffening. In conclusion, the results of the present study revealed that treatment with perindopril reduced SBP and PWV in SHR. In addition, the proteomic analysis in aorta suggested, for the first time, that the RhoA/Rho-kinase/Cofilin-1 pathway may be inhibited by perindopril-induced upregulation of GDIs or increases in NO bioavailability in SHR. Therefore, we may propose that activation of GDIs or inhibition of RhoA/Rho-kinase pathway could be a possible strategy to treat arterial stiffness.

Highlights

MATERIALS AND METHODSArterial stiffness has been recognized as an independent predictor of all-cause mortality, in population with diseases like hypertension, diabetes, and renal disease (Hamilton et al, 2007; Sakuragi and Abhayaratna, 2010; Vlachopoulos et al, 2010), and in overall population (Mitchell, 2014; Nilsson Wadstrom et al, 2019; Scuteri et al, 2020)
Even though it is not clear whether arterial stiffness precedes hypertension or it is a consequence (Kaess et al, 2012; Mitchell, 2014; Celik et al, 2017; Rode et al, 2020), several studies have shown a significant correlation between pulse wave velocity (PWV) and blood pressure (BP) (Laurent et al, 2009; Phillips et al, 2015; Steppan et al, 2020), including the present study, and the growing incidence of cardiovascular events in patients with high PWV values is eminent (Niiranen et al, 2017; Nilsson Wadstrom et al, 2019; Scuteri et al, 2020)
It is well known that angiotensin II (Ang II) plays a central role in hypertension due to its potent contractile action, and drugs that inhibit Ang II signaling are widely used to treat hypertension (Schmidt-Ott et al, 2000; Marque et al, 2002; Varagic et al, 2010; Gonzalez et al, 2018)

Summary

Introduction

MATERIALS AND METHODSArterial stiffness has been recognized as an independent predictor of all-cause mortality, in population with diseases like hypertension, diabetes, and renal disease (Hamilton et al, 2007; Sakuragi and Abhayaratna, 2010; Vlachopoulos et al, 2010), and in overall population (Mitchell, 2014; Nilsson Wadstrom et al, 2019; Scuteri et al, 2020). The possibility of having an experimental model with the measurement of both blood pressure (BP) and PWV, simultaneously with direct access to the arteries for gene, protein, histological studies, and other assays, represents an important advancement for better understanding the mechanisms involved in arterial stiffness changes. In this regard, our group recently standardized a new non-invasive device for assessment of arterial stiffness in rats (Fabricio et al, 2020) and showed that it is able to detect changes in arterial stiffness that are conditioned by age- and pressure-related arterial remodeling. Among several causes of aortic stiffness, the central role of the renin–angiotensin system (RAS) is well known, and some studies have shown the effects of RAS inhibition on arterial stiffness (Marque et al, 2002; Gonzalez et al, 2018) and, on BP, but the exact molecular mechanisms induced by RAS on aortic stiffness are not completely understood

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