# The transcriptional control of vascular calcification in disease

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $626,052

## Abstract

Cardiovascular diseases such as vascular calcification are a leading cause of death in patients with chronic
kidney disease (CKD). However, there is no effective therapy for vascular calcification available.
Phosphotoxicity and lipototoxicity are the major causes of CKD-dependent vascular calcification. Our long-term
goal is to identify new pharmacological strategies for the prevention of vascular calcification. Our previous
studies have demonstrated that stearic acid (C18:0), one of the major saturated fatty acids (SFAs), is a critical
metabolite that contributes to CKD-dependent vascular calcification. Mechanistically, CKD-mediated
hyperphosphatemia (high inorganic phosphate) induces the significant repression of VSMC stearoyl-CoA
desaturase (SCD), which is a major enzyme that controls levels of C18:0 by converting it to oleic acid (C18:1n-
9). Accumulation of C18:0 by SCD strongly induces severe lipotoxicity in VSMCs, resulting in vascular
calcification. In addition, our group has found that the pro-calcific effect of C18:0 is mediated by two major
metabolites of C18:0 generated via the enzyme reaction with glycerol-3-phosphate acyltransferase-4 (GPAT4):
1) 1,2-di-stearoyl-phosphatidic acid (18:0/18:0-PA), which induces vascular calcification through the activation
of the PERK-eIF2-ATF4 axis of the ER stress pathway and 2) 1-stearoyl-lysophoshatdic acid (18:0-LPA)
which strongly inhibits autophagic flux through the formation of abnormal MAM-associated omegasomes,
which are a platform for autophagosome formation. C18:0 induces vascular calcification through the activation
of the ER stress response and the inhibition of autophagy. However, the molecular mechanism underlying the
upstream event in which CKD-mediated hyperphosphatemia transcriptionally represses VSMC SCD has not
been studied. We believe that the identification of the mechanism has therapeutic potentials. To find clues of
the mechanism, we recently screened a library of chemicals that modulate epigenetics and gene transcription.
Based on the epigenetic and transcriptional chemical library screening, we identified two transcriptional
repressor candidates that contribute to phosphate-mediated SCD repression and vascular calcification. We
therefore propose two specific aims to elucidate the upstream event in the regulation of lipotoxicity-induced
vascular calcification. Aim 1 will examine whether the transcriptional repressor modulation complex affects
lipotoxicity and vascular calcification by altering SCD expression in cultured cells. Aim 2 will examine whether
modulation of transcriptional repressors affects phosphotoxicity, lipotoxicity and vascular calcification in vivo.
Completion of this project will provide a novel therapeutic target for CKD-mediated vascular calcification.

## Key facts

- **NIH application ID:** 10647475
- **Project number:** 1R01HL157064-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Makoto Miyazaki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $626,052
- **Award type:** 1
- **Project period:** 2023-03-15 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10647475

## Citation

> US National Institutes of Health, RePORTER application 10647475, The transcriptional control of vascular calcification in disease (1R01HL157064-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10647475. Licensed CC0.

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