# Potential therapies to improve ventricular vagal function in type 2 diabetes

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $381,250

## Abstract

Project Summary
Diabetes-reduced cardiac vagal activity is involved in sudden cardiac death and is responsible
for high mortality in diabetic patients. Increasing cardiac vagal tone significantly limits cardiac
dysfunction and reduces mortality. However, the potential mechanisms involved in reduced
cardiac vagal activity in type 2 diabetes mellitus (T2DM) are poorly understood. Cardiac vagal
ganglionic neurons (a final common pathway for vagal control of cardiac function) regulate
acetylcholine release to influence cardiac function. Ca++ influx through voltage-gated Ca++
channels is a key trigger for acetylcholine release from these neuronal terminals. Our recent
study has shown that expression and current density of N-type Ca++ channels in cardiac vagal
ganglionic neurons are decreased in T2DM rats. Rat cardiac vagal ganglia are divided into the
sinoatrial ganglion and the atrioventricular ganglion (AVG). The ventricular myocardium only
receives the projection of nerve terminals from AVG neurons. Based on our preliminary data, we
hypothesize that T2DM-mediated hydrogen peroxide (H2O2) overproduction in AVG
neurons inhibits N-type Ca++ channel function via repressor element 1-silencing
transcription factor (REST) signaling and/or by direct action, which further contributes to
attenuation of ventricular vagal neuronal function in T2DM. Using multi-faceted technical
approaches ranging from whole-animals to cellular-molecular levels, we will design in vivo and
in vitro studies in sham and T2DM rats to assess these questions. In Specific Aim 1, we will
address if T2DM induces ventricular vagal neuronal dysfunction as measured by N-type Ca++
channel expression and activation, cell excitability, and intracellular Ca++ levels in ventricular
vagal neurons, as well as ventricular acetylcholine release from vagal nerve terminals. In
Specific Aim 2, we will test how H2O2 overproduction modulates function of AVG neurons in
T2DM through REST signaling. In Specific Aim 3, we will determine if impairment of ventricular
vagal neurons contributes to ventricular electrical and contractile dysfunction in T2DM. These
studies will further our understanding of the cellular and molecular mechanisms responsible for
impaired cardiac vagal activity in T2DM and will also explore potential therapeutics for improving
cardiac vagal activity and reducing mortality in T2DM.

## Key facts

- **NIH application ID:** 9974572
- **Project number:** 5R01HL144146-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Yu-Long Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9974572

## Citation

> US National Institutes of Health, RePORTER application 9974572, Potential therapies to improve ventricular vagal function in type 2 diabetes (5R01HL144146-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9974572. Licensed CC0.

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