# Molecular Regulation of Vascular Calcification in Diabetes

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2020 · —

## Abstract

Vascular calcification and stiffness are hallmarks of diabetic vascular disorder, a prevalent cardiovascular
complication that leads to increased morbidity and mortality in the Veteran's population. The Veterans Affairs
Diabetes Trial has documented that vascular calcification was elevated in the Veterans, but the lipid-lowering
statins failed to inhibit the disease progression. Disrupted circadian clock is a common issue in military
personnel, which affects many of our Veterans. Abnormal circadian rhythm has been associated with
exacerbated diabetic cardiovascular disease. However, the role of abnormal circadian rhythm in accelerating
pathogenesis of diabetic vascular disease is not clear. Therefore, the current application aims to understand
how disruption of normal circadian rhythms may affect vascular calcification and stiffness in diabetes, which
would fill the unmet scientific gaps. Diabetes is often featured with both hyperglycemia and oxidative stress,
which are known to promote protein O-GlcNAcylation, a key posttranslational protein modification that regulates
numerous cellular processes. We have shown that in vascular smooth muscle cells (VSMC), elevated O-
GlcNAcylation/AKT/FOXO signaling induces the expression of the master calcification factor, Runx2, thus
promoting VSMC calcification. In preliminary studies, we uncovered a time-of-day oscillation of Runx2
expression along with BMAL1, the key circadian regulator, in mouse aortas in vivo and in VSMC in vitro. In
diabetic mouse arteries, elevation of O-GlcNAcylation and increased expression of BMAL1 were identified, which
was associated with upregulation of Runx2. Furthermore, using BMAL1 deficient VSMC, we determined a
causative regulation of O-GlcNAcylation in VSMC by BMAL1-dependent signals. Therefore, we hypothesize
that “Abnormal circadian rhythm promotes vascular calcification in diabetes through O-GlcNAcylation-
regulated FOXO/Runx2 signaling axis.” With our newly generated inducible SMC-specific OGT and BMAL1
deletion mouse models, the proposal will uncover a novel causative role of vascular circadian clock and O-
GlcNAcylation in regulating vascular calcification in diabetes; and delineate the underlying molecular
mechanisms. Outcomes from the proposed studies will advance our knowledge in understanding of the basic
mechanisms underlying pathogenesis of vascular calcification in diabetes, which should provide important
molecular insights into clinical implications in the developing successful therapy for vascular disease featuring
abnormal circadian clock and increased O-GlcNAcylation.

## Key facts

- **NIH application ID:** 9775753
- **Project number:** 1I01BX004426-01A1
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Yabing Chen
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9775753

## Citation

> US National Institutes of Health, RePORTER application 9775753, Molecular Regulation of Vascular Calcification in Diabetes (1I01BX004426-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9775753. Licensed CC0.

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