Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension

Andrew Stiegler,Vivek Shah,Jian-Hua Li,Huan Yang,Michael Brines,Tea Tsaava,Aisling Tynan,Kevin J Tracey,Yehuda Tamari,Sangeeta S Chavan

doi:10.1186/s10020-021-00380-6

Abstract

Acetylcholine (ACh) decreases blood pressure by stimulating endothelium nitric oxide-dependent vasodilation in resistance arterioles. Normal plasma contains choline acetyltransferase (ChAT) and its biosynthetic product ACh at appreciable concentrations to potentially act upon the endothelium to affect blood pressure. Recently we discovered a T-cell subset expressing ChAT (TChAT), whereby genetic ablation of ChAT in these cells produces hypertension, indicating that production of ACh by TChAT regulates blood pressure. Accordingly, we reasoned that increasing systemic ChAT concentrations might induce vasodilation and reduce blood pressure. To evaluate this possibility, recombinant ChAT was administered intraperitoneally to mice having angiotensin II-induced hypertension. This intervention significantly and dose-dependently decreased mean arterial pressure. ChAT-mediated attenuation of blood pressure was reversed by administration of the nitric oxide synthesis blocker l-nitro arginine methyl ester, indicating ChAT administration decreases blood pressure by stimulating nitic oxide dependent vasodilation, consistent with an effect of ACh on the endothelium. To prolong the half life of circulating ChAT, the molecule was modified by covalently attaching repeating units of polyethylene glycol (PEG), resulting in enzymatically active PEG-ChAT. Administration of PEG-ChAT to hypertensive mice decreased mean arterial pressure with a longer response duration when compared to ChAT. Together these findings suggest further studies are warranted on the role of ChAT in hypertension.

Highlights

100 million adults in the United States and more than 1 billion individuals worldwide have hypertension (Mozaffarian et al 2015), which is a major risk factor for cardiovascular disease, kidney disease, stroke and cognitive impairment (Pugh et al 2019; González et al 2018; Zhou et al 2018; World Health Organization 2013)
Here we report that administration of polyethylene glycol (PEG)-choline acetyltransferase (ChAT) to mice with angiotensin II (Ang II)-induced hypertension significantly attenuates increases in mean arterial blood pressure (MAP), systolic blood pressure (SBP) and diastolic blood pressure (DBP) without altering other physiological parameters including Heart rate (HR), temperature and activity
These findings reveal the previously unrecognized potential use of exogenous ChAT as an experimental therapeutic in hypertension

Summary

Introduction

100 million adults in the United States and more than 1 billion individuals worldwide have hypertension (Mozaffarian et al 2015), which is a major risk factor for cardiovascular disease, kidney disease, stroke and cognitive impairment (Pugh et al 2019; González et al 2018; Zhou et al 2018; World Health Organization 2013). Endothelial cells lining resistance arterioles are stimulated to mediate vasodilation when exposed to acetylcholine (ACh) which induces the release of nitric oxide (NO), termed endothelium derived. ACh interacts with muscarinic receptors expressed on endothelial cells, and receptor activation induces phosphorylation of endothelial nitric oxide synthase, the rate limiting enzyme in the biosynthesis of NO (Dimmeler et al 1999; Palmer et al 1988; Zhou et al 2005). NO produced by endothelial cells diffuses to adjacent smooth muscle cells, interacts with the heme group in souble guanylate cyclase to stimulate biosynthesis of cGMP, a secondary messenger. CGMP in turn activates signaling cascades to release calcium ion from intracellular stores which produces relaxation of smooth muscle cells and decrease in blood pressure

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