# Exosomes in the Pathogenesis of Diabetic Atherosclerosis & its Treatment Opportunities

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2024 · —

## Abstract

The goal of this proposal is to understand why people with diabetes develop severe fatty-rich plaques called
atherosclerosis in arteries. Atherosclerosis is linked to several cardiovascular diseases that cause disabilities
and premature death. Unfortunately, such serious medical problems are very frequent among veterans as they
are almost three times more likely to develop diabetes than people in the general population. One reason that
has been identified to enhance atherosclerosis among diabetic individuals is high blood sugar, often called
“hyperglycemia”. But exactly how hyperglycemia enhances atherosclerosis is not known.
Our research program aims to explore the role of microvesicles released by cells, called “exosomes”, as a source
of atherosclerosis. Our published and preliminary findings presented in our grant proposal show that both mice
and humans with diabetes accumulate exosomes in their bloodstream that can increase inflammatory signaling
when cultured with naïve cells. Our results also demonstrate that pro-inflammatory exosomes can be produced
by macrophages cultured in glucose-rich medium that we termed HG-exosomes. We found that HG-exosomes
simulate diabetic hyperglycemia by driving atherosclerosis when injected into non-diabetic mice. Remarkably,
we also uncovered that macrophages can produce anti-inflammatory exosomes when they are exposed to
protective cytokines such as interleukin-4. While we have reported that IL4-exosomes can exert protective effects
in suppressing atherosclerosis in non-diabetic mice, we do not know if they can do the same to control diabetic
atherosclerosis that is far more aggressive.
Based on our extensive findings, we propose to explore mechanisms through which HG-exosomes communicate
pro-inflammatory signaling in the immune system and the vessel wall. We also aim to investigate if IL4-exosomes
can serve to overcome the effects of hyperglycemia to suppress the progression of diabetic atherosclerosis.
Our First Aim will investigate molecular and cellular pathways through which HG-exosomes contribute to cause
cellular dysfunction in cultured macrophages. We will test if they do so by causing lipid accumulation and by
impairing the ability for macrophages to display protective anti-inflammatory activities that have been reported
to be critical in suppressing atherosclerosis, and are known to be defective in the setting of diabetes.
Our Second Aim will test if HG-exosome can communicate inflammatory signaling to fat cells called adipocytes
to increase their storage of oily lipids and thereby cause inflammatory signaling. We will also test if the injection
of HG-exosomes in to non-diabetic mice can cause them to develop diabetes as a result of increased visceral
fat accumulation, resulting in obesity and high blood glucose levels that then accelerate atherosclerosis. We will
test if IL4-exosomes can serve to prevent these effects to control atherosclerosis in obese diabetic mice.
Our Third Aim will test if HG...

## Key facts

- **NIH application ID:** 10702248
- **Project number:** 2I01BX003928-05
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** Robert Raffai
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2019-07-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10702248

## Citation

> US National Institutes of Health, RePORTER application 10702248, Exosomes in the Pathogenesis of Diabetic Atherosclerosis & its Treatment Opportunities (2I01BX003928-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10702248. Licensed CC0.

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