Neuronal cholinergic signaling constrains norepinephrine activity in the heart

• DOI: 10.1152/ajpcell.00031.2022
• Publication Date: 2022-03-10T01:29:30Z
• Authors: Diogo A. Guimarães; Nayara S. S. Aquino; Cibele Rocha-Resende; Itamar C. G. Jesus; Mario Morais Silva; Sérgio A. Scalzo; Roberta Cristelli...; Marina T. Durand; Vanessa Pereira; Geisa C. S. V. Te...; André Oliveira; Vania F. Prado; Ivanita Stefanon; Helio C. Salgado; Marco Antônio Máx...; Raphael E. Szawka; Silvia Guatimosim
• Keywords: Vesicular acetylcholine transporter

It is well known that cholinergic hypofunction contributes to cardiac pathology, yet, the mechanisms involved remain unclear. Our previous study has shown genetically engineered model of deficit, vesicular acetylcholine transporter knockdown homozygous (VAChT KDHOM) mice, exhibit pathological remodeling and a gradual increase in mass with aging. Given an often caused by adrenergic hyperactivity, we hypothesized VAChT KDHOM mice might have norepinephrine (NE) levels. We thus investigated temporal changes NE content heart from 3-, 6-, 12-mo-old mutants. Interestingly, showed elevation content, which was already increased at 6 mo age. Consistent this finding, 6-mo-old enhanced sympathetic activity greater abundance tyrosine hydroxylase positive nerves heart. mutants exhibited peak calcium transient, mitochondrial oxidative stress cardiomyocytes along G protein-coupled receptor kinase 5 (GRK5) nuclear factor activated T-cells (NFAT) staining These are targets signaling cell. Moreover, vagotomized-mice displayed confirming data obtained mice. Establishing causal relationship between NE, treated pyridostigmine, cholinesterase inhibitor, reduced rescuing phenotype. findings unveil yet unrecognized role as modulator providing novel insights into drive autonomic imbalance.