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Choline Acetyltransferase Administration Decrease Blood Pressure in a Murine Model of Hypertension
Author(s) -
Stiegler Andrew,
Li JianHua,
Shah Vivek,
Tsaava Tea,
Tynan Aisling,
Tamari Yehuda,
Chavan Sangeeta,
Tracey Kevin
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04623
Subject(s) - choline acetyltransferase , blood pressure , acetylcholine , medicine , endocrinology , nitric oxide , nitric oxide synthase , cholinergic , pharmacology
Despite significant advances in anti‐hypertensive therapy, more than half of hypertensive patients fail to control their blood pressure. The estimated morbidity associated with hypertension is over 30% worldwide, and many hypertensive patients progressively develop cardiovascular disease and chronic kidney disease. Thus, the development of novel antihypertensive therapies is required. Acetylcholine, released by cholinergic neurons and lymphocytes, is a major mediator of endothelium‐dependent, arterial smooth muscle relaxation that decreases blood pressure. Here, we assessed the effects of choline acetyltransferase (ChAT), a rate‐limiting enzyme in acetylcholine biosynthesis, on decreasing arterial blood pressure in a preclinical model of hypertension. Hypertension was induced in mice using subcutaneous infusion of angiotensin II via osmotic mini‐pumps. A single injection of ChAT beginning as late as two weeks after induction of hypertension decreases mean arterial blood pressure (MAP) (121 ± 4 mmHg vehicle vs 107 ± 8 mmHg ChAT, p = 0.06). Acetylcholine acts on muscarinic receptors on endothelial cells and produces arterial relaxation by activating endothelial nitric oxide (NO) synthase that produces NO from L‐arginine. To investigate whether ChAT administration stimulates these mechanisms of NO production, we pretreated mice with NOS inhibitor N ω ‐nitro‐L‐arginine methyl ester (L‐NAME), and measured blood pressure following administration of ChAT. Administration of L‐NAME significantly attenuates ChAT‐mediated decrease in blood pressure (4.3 ± 6.1 %MAP × h vs25.4 ± 4.9 %MAP × h, p = 0.02). To increase the stability and decrease the immunogenicity of the exogenous ChAT, the protein was PEGylated by covalently coupling polyethylene glycol with ChAT. Activity analysis revealed that PEGylated ChAT (PEG‐ChAT) retains enzymatic activity. A single intraperitoneal administration of PEG‐ChAT significantly reduces MAP as compared to vehicle injection (121 ± 4.5 mmHg vehicle vs 102 ± 4 mmHg PEG‐ChAT 1 mg/kg, p = 0.01). Finally, administration of ChAT and PEG‐ChAT during the sleep cycle produces a robust decrease in arterial blood pressure. These observations present administration of ChAT as a novel therapeutic strategy for preventing the progression of established hypertension.