# Critical Role of Small Extracellular Vesicles in Diabetic Coronary Vascular Dysfunction and Diabetic Ischemic Heart Failure efforts.

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2021 · $404,550

## Abstract

With continually improving reperfusion strategies, the overall mortality of AMI has been significantly reduced in
non-diabetic patients. However, both the prevalence and severity of ischemic heart failure (IHF) continually
escalate in patients with type 2 diabetes. Identifying risk factors, pathological mechanisms, and effective
interventions blocking diabetic exacerbation of IHF are urgently needed. Endothelial injury and resultant coronary
microvascular dysfunction (CMD) are the hallmarks of diabetic cardiovascular complications, hindering adequate
reperfusion despite successful recanalization. Clarifying mechanisms responsible for diabetic CMD and
identifying effective interventions improving coronary circulation are essential in reducing diabetic IHF
exacerbation. Research in the past decade has increased understanding of the roles adipocytes (ADp) play in
health and disease. Functional ADp are critical in maintaining systemic metabolic hemostasis, whereas ADp
dysfunction is one of the most recognized pathogenic factors leading to type 2 diabetes. A complete
understanding of the molecular mechanisms mediating the communication between adipose tissue and heart
will undoubtedly help the development of effective therapies against diabetic cardiovascular death. Extracellular
vesicles, particularly exosomes (Exo), are increasingly recognized as systemic messengers mediating inter-
cellular/inter-organ communication. Evidence from our recently published work and additional preliminary data
strongly suggest that GRK5-induced coronary microcirculatory endothelial cells (CMEC) adiponectin receptor 1
(AdipoR1) phosphorylation is responsible for attenuated ADp-derived Exo (ADp-Exo) protective signaling and
increased cytotoxic ADp-Exo uptake in diabetic CMEC, contributing to diabetic exacerbation of CMD and IHF.
Targeting the GRK5-AdipoR1 system may be a novel therapeutic intervention against diabetic CMD, ultimately
protecting the heart against IHF. This novel hypothesis will be rigorously investigated in 3 specific aims. Utilizing
genetic gain- and loss-of-function approaches, Specific Aim 1 will test a hypothesis that diabetes-induced CMEC
AdipoR1 phosphorylation blocks ADp-Exo mediated vasculoprotection, contributing to diabetic CMD and IHF
exacerbation. Specific Aim 2 will test a novel hypothesis that diabetic AdipoR1 phosphorylation and resultant
endocytosis promotes CMEC uptake of cytotoxic ADp-Exo via adiponectin (on ADp-Exo surface) interaction with
AdipoR1 (expressed in CMEC). Specific Aim 3 will determine whether 1) EC AdipoR1 phosphorylation mediates
diabetic ADp-Exo induced CMD and IHF, and 2) blocking EC AdipoR1 phosphorylation is effective in protecting
diabetes-exacerbated CMD and IHF. Successful completion of these studies will reveal a novel molecular
mechanism responsible for the diabetic exacerbation of cardiovascular injury, and potentially identify novel
therapy against CMD and post-MI remodeling in diabetic patients. Moreover, succ...

## Key facts

- **NIH application ID:** 10274392
- **Project number:** 1R01HL158612-01
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Yajing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,550
- **Award type:** 1
- **Project period:** 2021-07-05 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274392

## Citation

> US National Institutes of Health, RePORTER application 10274392, Critical Role of Small Extracellular Vesicles in Diabetic Coronary Vascular Dysfunction and Diabetic Ischemic Heart Failure efforts. (1R01HL158612-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10274392. Licensed CC0.

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