# Modulation of Protective RAS-GPCR Pathways in Aortic Disease

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $646,151

## Abstract

Project Summary
The renin-angiotensin system hormone angiotensin II (AngII) is a critical regulator of a number of
pathophysiological processes, including regulation of normal blood pressure and normal growth/survival of
cells in blood vessels. The type 1 receptor (AT1R) activation is a critical prerequisite for all AngII-mediated
pathophysiological processes, and consequently inhibition of the hormone functions by AT1R-blockers (ARBs)
is widely used to treat a wide spectrum of cardiovascular diseases. Three sequential signals are activated
when AngII binds to AT1R. First, the G protein Gq/11-PLC cascade initiates calcium mobilization leading to
muscle contraction or electrolyte/water flux. Second, GRK2/3 recruited to AngII-bound AT1R phosphorylates C-
terminal Ser/Thr residues which bind β-arrestin1/2 and promote internalization. The AT1R continues to signal in
endosomes causing long-term changes in gene transcription and protein synthesis. When the AT1R activation
becomes chronic, disease states such as vascular, renal and cardiac hypertrophy, aortic aneurism (AA), and
vascular fibrosis become prevalent. Genetic and pharmacological studies have shown that chronic G-protein
signaling by AT1R increases risk for tissue inflammation, oxidative damage and cell death.
 Nearly two decades ago we designed an analog of AngII, [Sar1,Ile4,Ile8]AngII (SII-AngII) which did not
stimulate G protein signaling, but effectively promoted internalization and intracellular ERK1/2 signaling. We
have now developed several high-affinity AT1R ligands that inhibit G-protein dependent AT1R signals and
enhance phosphorylation and internalization of AT1R associated with β-arrestin. Within cells, ERK1/2 associate
with β-arrestin-bound to AT1R leading to ERK1/2 activation restricted to the cytoplasm. This mode of signaling
has attained significance due to potential long-term benefits for cardiovascular homeostasis and an innovative
opportunity for new treatment modalities. However, the molecular mechanism of these novel AT1R ligands and
their in vivo efficacy in vascular disease models remains unclear. Our short-term objective is to test the
hypothesis that signals modulated by β-arrestin-biased AT1R ligands inhibit G-protein activation and will protect
aorta prone to AngII-induced damage in vivo. Our specific aims are: Aim 1. Determine the efficacy of β-
arrestin-biased AT1R ligands to protect vessels during aortic aneurism (AA) pathogenesis. Aim 2. Evaluate
genetic factors that influence AT1R/β-arrestin-biased signaling. Aim 3. Delineate the molecular mechanism of
coupling of AT1R to β-arrestin in vascular cells. These proposed studies will advance our knowledge of AT1R
signaling and may provide insights into new approaches for preventing tissue/organ hypertrophy and fibrosis.
Our long-term goal is to delineate mechanisms of β-arrestin-mediated signaling of AT1R as well as to develop
non-peptide AT1R-selective biased ligands for therapy.

## Key facts

- **NIH application ID:** 9932130
- **Project number:** 5R01HL142091-03
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Sadashiva S Karnik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $646,151
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932130

## Citation

> US National Institutes of Health, RePORTER application 9932130, Modulation of Protective RAS-GPCR Pathways in Aortic Disease (5R01HL142091-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932130. Licensed CC0.

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