Angiotensin III Induces JAK2/STAT3 Leading to IL-6 Production in Rat Vascular Smooth Muscle Cells

Ahmed Z Alanazi,Michelle A Clark

doi:10.3390/ijms20225551

Abstract

The Janus kinase-2/ signal transducer and activators of transcription-3 (JAK2/STAT3) pathway and interleukin-6 (IL-6) are pleiotropic signal transduction systems that are responsible for induction of many cytokines and growth factors. It is unknown whether the renin angiotensin aldosterone system (RAAS) peptide, angiotensin (Ang) III induces JAK2/STAT3 and IL-6 in vascular smooth muscle cells (VSMCs). Thus, the purpose of this study was to investigate whether Ang III induces the JAK2/STAT3 pathway leading to IL-6 production in cultured VSMCs isolated from Wistar rats and determine whether differences exist in spontaneously hypertensive rat (SHR) VSMCs. We gauged Ang III’s effects on this pathway by measuring its action on STAT3 as well as IL-6 production. Ang III behaved similarly as Ang II in stimulation of STAT3 phosphorylation in Wistar and SHR VSMCs. Moreover, there were no differences in this Ang III effect in SHR versus Wistar VSMCs. In Wistar VSMCs, Ang II and Ang III significantly induced IL-6 protein secretion and mRNA expression. However, IL-6 protein secretions mediated by these peptides were significantly greater in SHR VSMCs. Ang III induced the JAK2/STAT3 pathway, leading to IL-6 protein secretion and IL-6 mRNA expression via actions on AT1Rs. Moreover, the actions of Ang III to induce IL-6 production was dysregulated in SHR VSMCs. These findings suggest that Ang III acts on AT1Rs to induce JAK2/STAT3, leading to an increase in IL-6 in cultured VSMCs. These findings are important in establishing Ang III as an important physiologically relevant peptide in VSMCs.

Highlights

The renin-angiotensin aldosterone system (RAAS) is a peptide hormone system that contributes to various hypertensive disorders, such as renovascular hypertension, malignant hypertension, and renin-secreting neoplasms [1]
To establish and compare the effects of Ang peptides on STAT3 protein phosphorylation in the periphery, concentration and time curves studies were performed in cultured Wistar vascular smooth muscle cells (VSMCs)
Growth arrested VSMCs were incubated with increasing concentrations of Ang II and Ang III (0.1, 1, 10, 100, and 1000 nM) for 10 min to determine the concentration effects of the peptides on STAT3 phosphorylation

Summary

Introduction

The renin-angiotensin aldosterone system (RAAS) is a peptide hormone system that contributes to various hypertensive disorders (secondary hypertensions), such as renovascular hypertension, malignant hypertension, and renin-secreting neoplasms [1]. The angiotensin (Ang) type 1 receptor (AT1R) and the Ang type 2 receptor (AT2R) are responsible for mediating the physiological and pathological actions of Ang II and Ang III [4,5]. These receptors generally have opposite physiological effects [6]. Ang III mediates several physiological functions in a similar manner to Ang II by activation of AT1Rs [7]. The two peptides are very similar (one amino acid difference) in structure

Objectives

Methods

Results