Manipulating Hepatic GABA Production and Release to Affect Changes in Blood Pressure
Abstract
This project directly addresses the hypertension topic area. In 2004, health risk assessments of U.S. Service Members at Fort Lewis showed that 13% of subjects were hypertensive and 62% of U.S. Service Members were pre-hypertensive. Thirty percent of U.S. military Veterans are hypertensive, and the incidence is exacerbated in those who faced combat during their deployment. Importantly, the results of these studies were reported before the thresholds for definition of hypertension were lowered from 140/90 to 130/80 mmHg in 2017, a change estimated to increase the percentage of individuals with hypertension by 14%. Among our general U.S. population, nearly 45% of people have hypertension and only one-quarter of those with hypertension are controlling their blood pressure. Obesity is the leading risk factor for the incidence of hypertension, increasing the risk of hypertension six times. Hypertension is the leading risk factor for the development of coronary heart disease and stroke, two leading cause of death in the U.S. Studies to understand the link between obesity and hypertension have established a strong relationship between the incidence and severity of hepatic lipid accumulation and hypertension. Interestingly, non-alcoholic fatty liver disease is directly linked to the prevalence of coronary artery calcification developing cardiovascular disease 2.56 times and 5.3 times. Still, the mechanism by which fatty liver might affect blood pressure remains relatively ambiguous. The peripheral nervous system provides a conduit by which the peripheral organs can communicate with the central nervous system and the central nervous system can communicate with the periphery. We show that the liver releases an inhibitory neurotransmitter, gamma-amino butyric acid (GABA), in relation to liver fat content. In fact, as liver fat increases, liver GABA release increases. This GABA alters activity of the peripheral nervous system, which actively regulates blood pressure. Our preliminary data suggests that increasing GABA release from the liver increases blood pressure. A phenotype we would expect since fatty liver, which is associated with hypertension, increases GABA release. Importantly, we have established that inhibition of hepatic GABA production decreases blood pressure in obese, angiotensin II induced hypertensive mice. We have seen that obesity alters liver expression of GABA transporters in people, suggesting the translational potential of this work. We propose two aims that will establish the key role of hepatic GABA in regulating blood pressure while investigating the effect of liver GABA on vasoactive hormones and parasympathetic and sympathetic nervous system activity. Aim 1: To establish the causative role of hepatocyte-produced GABA in stimulating a pressor response by activating sympathetic signaling on vascular smooth muscle. Aim 2: To assess the impact of overexpression a hepatic GABA export protein, TauT, or a hepatic GABA reuptake transporter, BGT1, on blood pressure and sympathetic tone on vascular smooth muscle. We propose to investigate a novel mechanism by which obesity, the leading cause of hypertension, may dysregulate blood pressure resulting in hypertension. Through this proposal, we will evaluate the therapeutic potential of inhibiting GABA production and release or increasing hepatic GABA re-uptake, in turn, identifying multiple modes to affect blood pressure and creating many pharmacological targets. Importantly, there are U.S. Food Administration-approved GABA transaminase inhibitors that have few peripheral side effects and would be expected to have a favorable safety profile after modification to prevent blood brain-barrier penetrance. We are excited by the potential that exists to allow for translation into the human and a better understanding of the mechanism by which fatty liver causes hypertension.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210043
Entities
People
- Benjamin Renquist
Organizations
- United States Army
- University of Arizona