# SUMO2-p66shc axis in vascular endothelial dysfunction and atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2021 · $418,921

## Abstract

ABSTRACT
 SUMOylation is a dynamic post-translational modification which involves the
conjugation of SUMOs (Small Ubiquitin-Like Modifiers) to the lysine residue/s of target
proteins affecting their function, localization or stability. Recent studies have reported
that SUMOylation (SUMO2/3) promotes vascular endothelial dysfunction and
accelerates atherosclerosis. This application aims to explore a redox-dependent
mechanism for the deleterious effect of SUMO2ylation in the vasculature, and identify a
novel target of SUMO2 in the vascular endothelium.
 We have observed that SUMO2 overexpression in endothelial cells promotes
oxidative stress and impairs endothelial function via the master redox regulator p66Shc.
Furthermore, we have observed that p66Shc is directly modified by SUMO2 on a critical
lysine that regulates the oxidative property of p66Shc. Based on this evidence, we
hypothesize that SUMO2ylation of p66Shc is a key molecular mechanism driving
vascular oxidative stress, endothelial dysfunction, and atherosclerosis.
 We have generated endothelium-specific SUMO2 transgenic mice, as well as
transgenic mice expressing non-SUMO2ylatable p66Shc in the endothelium, and whole
body knockin mice expressing non-SUMO2ylatable p66Shc. We will leverage these
mice, as well as tools to manipulate SUMO2ylation of p66Shc in vitro, to answer three
fundamental questions: 1) does SUMO2 expression in the endothelium promote
endothelial dysfunction and accelerate atherosclerosis; 2) is SUMO2ylation of p66Shc
responsible for SUMO2-induced endothelial dysfunction and atherosclerosis; and 3)
how does SUMO2ylation of p66shc promote endothelial oxidative stress.
 Answers to these important questions will establish the role of SUMO2 as a post-
translational modification that impairs vascular endothelial function and promotes
atherosclerosis via p66Shc. Advancing this knowledge could potentially lead to SUMO2-
directed therapies for atherosclerotic vascular disease.

## Key facts

- **NIH application ID:** 10129426
- **Project number:** 5R01HL152132-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Santosh Kumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,921
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129426

## Citation

> US National Institutes of Health, RePORTER application 10129426, SUMO2-p66shc axis in vascular endothelial dysfunction and atherosclerosis (5R01HL152132-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129426. Licensed CC0.

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