# Tension-induced SGK-1 Signaling in AAA

> **NIH NIH K08** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2022 · $176,472

## Abstract

Hypertension (HTN) is a major risk factor for cardiovascular mortality and greater than 30% of Americans
are currently affected. The impact of elevated blood pressure on aortic wall remodeling has significant
implications for vascular disease in general, and aneurysm formation specifically. AngiotensinII (AngII) is a potent
vasoactive peptide and contributes to vascular inflammation by stimulating production of interleukin-6 (IL-6) and
monocyte chemoattractant protein-1 (MCP-1) to augment the population of macrophages within the aortic wall.
Interestingly, patients with abdominal aortic aneurysms (AAA) have also consistently demonstrated elevated
plasma and aortic tissue levels of IL-6, along with dense macrophage infiltration. Defining the tension-induced
kinase driving cytokine production is vital to identifying a potential target for pharmacotherapy of AAA. Recent
evidence has identified serum and glucocorticoid inducible kinase-1 (SGK-1) as a mechanically sensitive kinase
that contributes to intimal hyperplasia, atherosclerosis, and pulmonary hypertension, and its downstream
regulation of several transcription factors can modulate the production of IL-6 and MCP-1. Therefore, it is
hypothesized that HTN promotes VSMC activation of SGK-1 to produce pro-inflammatory cytokines that
accumulate macrophages to propagate AAA growth. The first specific aim will analyze tension-induced SGK-1
activation and cytokine expression from aortic VSMCs harvested from C57Bl/6 wild-type and SGK-1 knockout
(SGK-1KO) mice. The ability of this conditioned media to stimulate monocyte/macrophage migration through a
permeable membrane will also be assessed. In the second aim, C57Bl/6 and SGK-1KO mice with induced HTN
(via AngII infusion) will be evaluated for the activation of SGK-1, production of pro-inflammatory cytokines IL-6
and MCP-1, and accumulation of macrophages. Dependence of this inflammatory response on SGK-1 activity
will be further explored by treating wild-type mice subjected to induced HTN with the selective SGK-1 inhibitor
EMD638683. The third specific aim will focus on the role of SGK-1 in initiating and propagating AAA formation
by employing a validated model of AAA induction with CaCl2 application and treating mice with EMD638683. The
terminal procedure will evaluate AAA diameter and production of target cytokines and proteases. The opportunity
for elevated tension to augment this effect will be explored by inducing HTN and concurrent AAA in the two
mouse strains and conducting parallel biochemical analysis. By establishing this link between HTN,
inflammation, and the initiation of degradative vascular remodeling through the activity of SGK-1, future studies
may utilize targeted inhibitor therapies to attenuate aneurysmal degeneration in the abdominal aorta. Moreover,
the experimentation outlined in this project will provide an opportunity for Dr. Ruddy to engage the resources of
MUSC and the Cardiovascular Research Laboratory to expand her research...

## Key facts

- **NIH application ID:** 10368068
- **Project number:** 5K08HL143169-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Jean Marie Ruddy
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $176,472
- **Award type:** 5
- **Project period:** 2019-04-14 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368068

## Citation

> US National Institutes of Health, RePORTER application 10368068, Tension-induced SGK-1 Signaling in AAA (5K08HL143169-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10368068. Licensed CC0.

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