# Coronary Endothelial Cell Dysfunction in Diabetes: Role of MFGE8

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2024 · $570,910

## Abstract

Program Summary/Abstract
Diabetes is a global epidemic. Many patients with diabetes suffer from and die of heart disease or stroke. Diabetic
heart diseases include diabetic cardiomyopathy, obstructive coronary artery disease (CAD), and coronary
microvascular disease (CMD, also known as non-obstructive CAD). Obstructive CAD is primarily caused by
narrowed vessels due to lipid plaque formation. In contrast, the mechanisms responsible for CMD are
microvascular rarefaction, attenuated vasodilatation, and vascular remodeling in small coronary arteries (CAs).
Coronary endothelial cell (EC) dysfunction leads to decreased capillary density in the heart and attenuated
endothelium-dependent relaxation in CAs, and diabetes causes endothelial dysfunction. However, there is no
specific treatment for coronary endothelial dysfunction in patients with diabetes. Our long-term goal is to define
the mechanisms of diabetes-associated coronary endothelial dysfunction and ultimately develop novel therapies
for CMD in diabetes. Milk fat globule epidermal growth factor (MFGE8) is a glycoprotein primarily secreted from
apoptotic cells and initially identified as an immune suppressor by assisting apoptotic cell clearance
(efferocytosis). MFGE8 is also capable of promoting angiogenesis and facilitating macrophage reprogramming.
MFGE8 administration exerts beneficial effects on cardiovascular disease, including anti-inflammation, tissue
repairing, and compensated cardiac hypertrophy; however, the role of MFGE8 in coronary endothelial
dysfunction and CMD in diabetes has never been investigated. The objective of this study is to examine
whether and how MFGE8 improves CMD in diabetes. Our preliminary data show that i) cardiac ECs from diabetic
mice and diabetic patients displayed lower MFGE8 levels than their controls, ii) Mfge8-/- mice exhibited reduced
coronary flow velocity reserve (CFVR), iii) inhibition of MFGE8 attenuated endothelium-dependent relaxation in
CAs and endothelial migration, iv) chronic administration of MFGE8 in diabetic mice improved CFVR
accompanied with increased capillary density in the heart, v) macrophages enabled to engulf apoptotic ECs ex
vivo, and MFGE8 pretreatment increased macrophage efferocytosis of ECs, and vi) MFGE8 administration in
diabetic mice facilitated reprogramming of macrophages to an anti-inflammatory phenotype. Based on these
data, we hypothesize that MFGE8 administration is a novel therapeutic strategy in diabetic patients with CMD
by improving coronary endothelial function and enhancing macrophage engulfment of apoptotic ECs in the heart
where MFGE8 level is reduced in coronary ECs. Three Specific Aims are proposed to test our novel hypothesis:
1) to define the role of MFGE8 in coronary endothelial dysfunction and CMD in diabetic mice, 2) to determine
the molecular mechanisms by which MFGE8 regulates coronary endothelial function in diabetes, and 3) to
investigate the role of MFGE8-mediated macrophage efferocytosis of coronary EC...

## Key facts

- **NIH application ID:** 11210718
- **Project number:** 7R01HL142214-06
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Yun Sok Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $570,910
- **Award type:** 7
- **Project period:** 2018-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11210718

## Citation

> US National Institutes of Health, RePORTER application 11210718, Coronary Endothelial Cell Dysfunction in Diabetes: Role of MFGE8 (7R01HL142214-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11210718. Licensed CC0.

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