# Mechanistic insights into the deleterious effects of SIRT2 in the heart under stress conditions

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $573,568

## Abstract

Heart failure (HF) is a major health epidemic in the developed countries; however, the underlying molecular
mechanisms for this disorder are not well characterized. Sirtuins (SIRT) are proteins that exhibit deacetylation
or ADP-ribosyltransferase activity and regulate a wide range of cellular processes. There are seven SIRTs in
mammalian cells that reside in the nucleus, mitochondria or cytoplasm, and modify certain proteins in their
respective cellular compartments. Nuclear and mitochondrial SIRTs are known to contribute to cardiac
protection, but the role of SIRT2 (the only sirtuin that resides predominantly in the cytoplasm) in the heart is not
known. We are addressing this fundamental gap in knowledge, and our strong preliminary data indicate that the
levels of SIRT2 are increased in failing human and mouse hearts. Furthermore, the hearts of mice with global
deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload
(PO). Thus, SIRT2 may have detrimental effects in the heart under stress conditions, which makes this protein
a unique member of the SIRT family. Furthermore, our mechanistic studies suggest that SIRT2 modulates
cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), a transcription factor that induces
the expression of antioxidant proteins. Finally, using mass spectrometry and site-directed mutagenesis, we have
identified specific lysine residues in NRF2 that are targeted by SIRT2. The central hypothesis of this proposal
is that SIRT2 exerts detrimental effects in the heart through deacetylation of NRF2, resulting in a
reduction in its protein levels and transcriptional activity, thereby decreasing the expression of
antioxidant proteins. In Aim 1, we will determine whether SIRT2 exerts deleterious effects in the heart in
response to injury, and whether the protection noted in Sirt2-/- mice is due to systemic or cardiac-specific deletion
of Sirt2. We will subject cardiac specific Sirt2 knockout (cs-Sirt2-/-) mice and mice with overexpression of SIRT2
to PO and will assess cardiac function, as well as reactive oxygen species (ROS) levels using novel fluorescence
markers. In Aim 2, we will study whether SIRT2 regulates NRF2 abundance and gene transcriptional activity by
deacetylating specific lysine residues within its DNA-binding and ubiquitination domains. We will assess total
and nuclear NRF2 levels, and its ubiquitination and transcriptional activity in the hearts of cs-Sirt2-/- mice at
baseline and after PO and in mouse embryonic fibroblasts (MEFs) with Sirt2 knockdown. We will also measure
NRF2 total and nuclear levels and transcriptional activity with overexpression of NRF2 mutant constructs with
mutation of SIRT2-targetd lysines to acetylated- or deacetylated-mimetic residues. In Aim 3, we will determine
whether the deleterious effects of SIRT2 in response to injury are mediated through NRF2. cs-Sirt2-/- and cs-
Sirt2-/-/Nrf2-/- mice will ...

## Key facts

- **NIH application ID:** 10071879
- **Project number:** 5R01HL138982-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Hossein Ardehali
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $573,568
- **Award type:** 5
- **Project period:** 2017-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071879

## Citation

> US National Institutes of Health, RePORTER application 10071879, Mechanistic insights into the deleterious effects of SIRT2 in the heart under stress conditions (5R01HL138982-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071879. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*