# Excess O-GlcNAc modification of proteins and myocardial fibrosis

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2020 · —

## Abstract

The major hypothesis to be tested in this proposal is that, “Reducing the excess addition of β-N-
acetylglucosamine (O-GlcNAc) to regulatory factors present in cardiac fibroblasts ameliorates diabetes mellitus
induced myocardial fibrosis”. Given the older average age of the Veteran population, about 25% suffer from
type 2 diabetes mellitus (DM2). A large number of these patients will develop DM2 induced cardiac fibrosis,
which adversely impacts diastolic function and frequently leads to the development of heart failure. Excess O-
GlcNAc modification of proteins is known to occur with aging and most notably in the setting of DM2. We have
demonstrated that excess O-GlcNAcylation of cardiac fibroblast (CF) proteins is associated with the enhanced
production of collagens. As tissue fibrosis (e.g. glomerulosclerosis) is a prominent feature of DM2 our research
findings may also have broader implications as a strategy to ameliorate excess collagen production by
fibroblasts present in other organs. The post-translational modification of serine and threonine residues of
nuclear and cytoplasmic proteins by the O-linked attachment of the monosaccharide β-N-acetylglucosamine is
a highly dynamic and ubiquitous protein modification that is secondary to the action of β-N-
acetylglucosaminyltransferase (OGT). Conversely, the removal of O-GlcNAc is mediated by N-
acetylglucosaminidase (O-GlcNAcase). Protein O-GlcNAcylation is rapidly emerging as a key regulator of
critical biological processes including nuclear transport, translation and transcription, signal transduction,
cytoskeletal reorganization, proteasomal degradation, and apoptosis. We demonstrated that in high glucose
treated CF, the nuclear transcription factor Sp1 and arginase evidence excess O-GlcNAcylation. Both of these
proteins are intricately associated with stimulating the production of collagens. Expression in CF of an
adenovirus coding for O-GlcNAcase, decreased Sp1 and arginase O-GlcNAcylation and restores high glucose-
induced excess collagen production back to normal levels. However, no studies have identified which specific
amino acid residues can be modified by O-GlcNAcylation and how they alter Sp1 and arginase function.
Furthermore, these observations have not been evidenced in the in vivo setting and linked with changes in
cardiac structure and function. Given these facts and the preliminary data we have generated, we propose to
examine the following specific aims: Aim 1. To identify the development of myocardial fibrosis, diastolic
dysfunction, Sp1 and arginase I residue modification in an aged model of DM2. Aim 2. To characterize HG
induced CF amino acid residue O-GlcNAc modification of Sp1 and arginase I and its functional implications.
Aim 3. To characterize the capacity of altered O-GlcNAcase activity to modify DM2 or HG induced alterations
in Sp1 and arginase I residue modification, fibroblast/myofibroblast phenotype, cardiac structure and function.

## Key facts

- **NIH application ID:** 9859307
- **Project number:** 5I01BX003230-03
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** Francisco J Villarreal
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859307

## Citation

> US National Institutes of Health, RePORTER application 9859307, Excess O-GlcNAc modification of proteins and myocardial fibrosis (5I01BX003230-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859307. Licensed CC0.

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