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

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.

Intrarenal Renin Angiotensin System Imbalance During Postnatal Life Is Associated With Increased Microvascular Density in the Mature Kidney

“…This data suggests that anti-angiogenic effects mediated by Ang 1–7 could be dramatically attenuated, thus promoting further vessel development ( van Esch et al, 2008 ; Pei et al, 2016 ; Touyz and Montezano, 2018 ). Furthermore, it has been shown that AngIII pro-angiogenic effects are mediated by both AT1 and AT2 receptors binding ( Kawasaki et al, 1988 ; Cheng et al, 1994 ; Del Borgo et al, 2015 ; Alanazi and Clark, 2019 , 2020 ). Therefore, our data suggests that in the context of glucocorticoid stimulation due to chronic stress, the upregulation of several RAS components could be a major player in the increased renal vascular density via the overstimulation of the AT1 and AT2 receptors along with the reduced Ang 1–7 anti-angiogenic effects.…”

Effect of profilin‐1 on the asymmetric dimethylarginine‐induced vascular lesion‐associated hypertension

“…The JAK2/STAT3 pathway serves as a crucial downstream mediator for the signal transduction of a variety of hormones, cytokines, and growth factors 29 . It has been shown that JAK activation is involved in the proliferation of VSMCs， and Ang II through the JAK2/STAT3 pathway increases nitroxidative stress, which contributes to the hyperproliferation of VSMC 30,31 . The study revealed that 7‐ketocholesterol upregulated profilin‐1 expression in aortic endothelial cells by activating the OSBP1/STAT3 pathway 32 .…”

Quercetin inhibits angiotensin II-induced vascular smooth muscle cell proliferation and activation of JAK2/STAT3 pathway: A target based networking pharmacology approach

“…The pathophysiology of EH is a highly complex mechanism. Multiple signaling-associated pathways, including the JAK2/STAT3 pathway, play a significant function in the pathophysiology of EH ( Mladěnka et al, 2018 ; Alanazi and Clark, 2019 ). Bioavailability of quercetin has been found to be involved in anti-hypertension, specially EH.…”