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

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2020 · —

## Abstract

The goal of this proposal is to understand why people with diabetes develop severe fatty-rich plaques called
atherosclerosis in arteries. Accelerated atherosclerosis has been linked to several types of cardiovascular
diseases that cause disabilities and premature death amongst diabetic individuals. Unfortunately, such serious
medical problems are very frequent among veterans enrolled in the VHA Health Care System 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, also called “hyperglycemia”.
But exactly how hyperglycemia enhances atherosclerosis is not known.
Our recent research focus has centered on exploring the role of microvesicles released by cells, called
“exosomes”, as a source of inflammation in atherosclerosis. Preliminary findings presented in our revised grant
proposal show that human diabetic subjects diagnosed with advance peripheral atherosclerotic cardiovascular
disease accumulate pro-inflammatory exosomes in their bloodstream. Our findings also show that diabetic mice
accumulate pro-inflammatory exosomes in their bloodstream. Furthermore, our findings show that such diabetic
plasma exosomes can increase the number of white blood cells that accumulate in arteries when they are infused
into non-diabetic mice. Interestingly, our data demonstrate that pro-inflammatory exosomes can be produced by
macrophages cultured in glucose-rich medium that simulates diabetic hyperglycemia. Remarkably, our data also
show that macrophages can produce anti-inflammatory exosomes when they cultured in medium that contains
protective cytokines such as interleukin-4.
Based on our extensive new findings, we propose to explore whether diabetic hyperglycemia enhances the
progression of atherosclerosis through exosomes that communicate pro-inflammatory signaling in the immune
system and the vessel wall. We also aim to produce exosomes that can serve to overcome the effects of
hyperglycemia to suppress the progression of diabetic atherosclerosis.
In our First Aim we will define the extent to which hyperglycemia causes the production of proinflammatory
exosomes in the bloodstream of veterans suffering from advanced atherosclerotic disease. We will do the same
by studying mouse models of diabetes. Next, we will test the ability of diabetic plasma exosomes to enhance
vascular inflammation and atherosclerosis when infused into hyperlipidemic mice. We will also test whether
macrophages cultured in medium that contains elevated levels of glucose or bad cholesterol called oxLDL, will
produce exosomes that can induce atherosclerosis when infused into non-diabetic mice. Lastly, we will explore
if a class of signaling molecule called microRNA carried by exosomes are responsible for their inflammatory
signaling.
In our Second Aim we will seek to produce therapeutic exosomes. Our strategy will consist of isolati...

## Key facts

- **NIH application ID:** 9983469
- **Project number:** 5I01BX003928-02
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** Robert Raffai
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983469

## Citation

> US National Institutes of Health, RePORTER application 9983469, Exosomes in the Pathogenesis of Diabetic Atherosclerosis & its Treatment Opportunities (5I01BX003928-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9983469. Licensed CC0.

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