# Coronary Endothelial Cell Dysfunction in Diabetes: Role of HuR

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $394,358

## Abstract

Program Summary/Abstract
Coronary micro- and macrovascular disease is the leading cause of diabetes-associated death. Despite many
medications for diabetes, the number of deaths resulting from coronary vascular complications is still high among
diabetic patients. Coronary vascular endothelial injury and dysfunction reduce coronary blood flow by inhibiting
vasodilatation and decreasing capillary density in the heart. Sustained coronary flow reduction not only increases
the risk to exaggerate cardiac damage after ischemia/reperfusion, but also leads to cardiac dysfunction. Our
long-term goal is to define the mechanisms of diabetes-associated coronary endothelial dysfunction and
ultimately develop novel therapies for coronary microvascular disease in diabetes. Posttranscriptional regulation
of gene expression is a critical step in mRNA biogenesis. The RNA-binding protein HuR serves as a key regulator
of mRNA stability and translation via binding to specific elements within mRNAs. The objective of this study is
to examine if HuR contributes to the development of coronary endothelial dysfunction in diabetes by regulating
hexokinase 2 (HK2), a modifier of mitochondrial [Ca2+], and connexin 40 (Cx40), a key component of gap junction
(GJ) in endothelial cells (ECs). We will use a) inducible and genetically modified diabetic mice (type 1 and type
2 diabetic mice) for in vivo and ex vivo experiments, b) mouse coronary ECs (MCECs) freshly-isolated from
control and diabetic mice and human coronary ECs (HCEC) from control subjects and diabetic patients for
molecular biological and electrophysiological experiments, and c) small coronary arteries (CAs, 3rd or 4th order)
for isometric tension experiments. Our preliminary data indicate that i) HuR deletion in ECs lowered coronary
flow velocity reserve and cardiac contractility, increased EC apoptosis, and decreased capillary density in the
heart, ii) protein levels of HuR, HK2 and Cx40 were decreased in diabetic HCECs and MCECs compared to the
controls, iii) HuR binds to Cx40 and HK2 mRNAs and increases their protein expression, iv) overexpression of
HuR, HK2 or Cx40 in diabetic ECs restored endothelial function to the level close to control ECs. Based on these
data, we hypothesize that downregulation of HuR leads to coronary endothelial dysfunction and subsequently
results in coronary microvascular disease in diabetes via downregulation of HK2 and Cx40 in ECs. Three
Specific Aims are proposed to test the hypothesis: 1) To explore the role of HuR in the development of
endothelial dysfunction in diabetic mice, 2) To characterize the HuR-mediated posttranscriptional modification of
HK2 and to examine whether HK2 contributes to coronary endothelial dysfunction in diabetes via mitochondrial
Ca2+ overload, and 3) To examine whether HuR regulates Cx40 expression levels and if overexpression of HuR
restores GJ intercellular communication through increasing Cx40 levels, enhances vascular relaxation, and
improves cardiac ...

## Key facts

- **NIH application ID:** 9867739
- **Project number:** 5R01HL142214-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ayako Makino
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,358
- **Award type:** 5
- **Project period:** 2018-03-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867739

## Citation

> US National Institutes of Health, RePORTER application 9867739, Coronary Endothelial Cell Dysfunction in Diabetes: Role of HuR (5R01HL142214-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867739. Licensed CC0.

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