Project Summary Diabetes-induced imbalance of autonomic efferent neuronal tone (reduced parasympathetic activity and increased sympathetic activity) is involved in sudden cardiac death and is responsible for high mortality in diabetic patients. Increasing cardiovascular vagal tone significantly reduces the mortality. Although cardiovascular vagal function is severely damaged in diabetic patients, the potential mechanisms concerning reduced cardiovascular vagal function in diabetes are poorly understood. Cardiovascular postganglionic vagal neurons in intracardiac ganglia modulate the acetylcholine release via producing cell excitation and finally regulate cardiovascular function. Our previous studies have shown that nicotinic acetylcholine receptor (nAChR) currents and cell excitability are reduced in vagal neurons, which contribute to cardiovascular vagal dysfunction in type 2 diabetes mellitus (T2DM). Based on our previous studies and preliminary data, we hypothesize that leptin resistance-uncoupling protein 2 (UCP2)-hydrogen peroxide (H2O2) signaling pathway and norepinephrine- α1 adrenergic receptor-UCP2-H2O2 axis inactivate nAChR channels and further contribute to cardiovascular vagal dysfunction in T2DM. Using multi-faceted technical approaches (from whole animals to cellular-molecular levels) in sham and high-fat diet/low-dose streptozotocin-induced T2DM rats, we design in vivo and in vitro studies to verify above hypotheses. In Specific Aim 1, we will measure if H2O2 overproduction in vagal postganglionic neurons decreases nAChR currents and induces cardiovascular vagal dysfunction in T2DM. In Specific Aim 2, we will test if leptin/leptin receptors influence nAChR currents and cardiovascular vagal function in T2DM. In Specific Aim 3, we will determine if sympathetic neurotransmitter norepinephrine-α1 adrenergic receptor axis reduces nAChR currents and cardiovascular vagal function in T2DM. These studies will further our understanding of the cellular and molecular mechanisms underlying the impairment of vagal neuronal function in T2DM and will discover potential therapeutic targets for improving cardiovascular vagal function and reducing mortality in the T2DM state.

Project Narrative Our previous studies have found decreased acetylcholine receptor currents and cell excitability in cardiac vagal neurons are associated with cardiac vagal dysfunction, which contributes to the high mortality in patients with type 2 diabetes mellitus. This proposal will focus on the potential mechanisms responsible for cardiac vagal neuronal dysfunction in T2DM. The significance of this project is to provide potential strategies to improve cardiac vagal function and to reduce mortality in patients with T2DM.