Activation of the cardiac non-neuronal cholinergic system prevents the development of diabetes-associated cardiovascular complications.
Acetylcholine
/ metabolism
Acetylcholinesterase
/ metabolism
Aged
Animals
Case-Control Studies
Choline O-Acetyltransferase
/ genetics
Diabetes Mellitus, Type 2
/ complications
Diabetic Cardiomyopathies
/ etiology
Disease Models, Animal
Female
GPI-Linked Proteins
/ metabolism
Glucose
/ metabolism
Glucose Transporter Type 4
/ metabolism
Heart Ventricles
/ metabolism
Humans
Male
Membrane Transport Proteins
/ metabolism
Mice, Inbred C57BL
Mice, Transgenic
Receptor, Muscarinic M2
/ metabolism
Symporters
/ metabolism
Vesicular Acetylcholine Transport Proteins
/ metabolism
Acetylcholine
Angiogenesis
Diabetic heart disease
Glucose metabolism
Non-neuronal cholinergic system
Journal
Cardiovascular diabetology
ISSN: 1475-2840
Titre abrégé: Cardiovasc Diabetol
Pays: England
ID NLM: 101147637
Informations de publication
Date de publication:
22 02 2021
22 02 2021
Historique:
received:
12
11
2020
accepted:
29
01
2021
entrez:
23
2
2021
pubmed:
24
2
2021
medline:
6
10
2021
Statut:
epublish
Résumé
Acetylcholine (ACh) plays a crucial role in the function of the heart. Recent evidence suggests that cardiomyocytes possess a non-neuronal cholinergic system (NNCS) that comprises of choline acetyltransferase (ChAT), choline transporter 1 (CHT1), vesicular acetylcholine transporter (VAChT), acetylcholinesterase (AChE) and type-2 muscarinic ACh receptors (M Ventricular samples from type-2 diabetic humans and db/db mice were used to measure the expression pattern of NNCS components (ChAT, CHT1, VAChT, AChE and M Immunoblot analysis revealed alterations in the components of cardiac NNCS and GLUT-4 in the type-2 diabetic human and db/db mouse hearts. Interestingly, the dysregulation of cardiac NNCS was followed by the downregulation of GLUT-4 in the db/db mouse heart. Db/db-ChAT-tg mice exhibited preserved cardiac and vascular function in comparison to db/db mice. The improved function was associated with increased cardiac ACh and glucose content, sustained angiogenesis and reduced fibrosis. These beneficial effects were associated with upregulation of the PI3K/Akt/HIF1α signaling pathway, and increased expression of its downstream targets-GLUT-4 and VEGF-A. We provide the first evidence for dysregulation of the cardiac NNCS in DHD. Increased cardiac ACh is beneficial and a potential new therapeutic strategy to prevent or delay the development of DHD.
Sections du résumé
BACKGROUND
Acetylcholine (ACh) plays a crucial role in the function of the heart. Recent evidence suggests that cardiomyocytes possess a non-neuronal cholinergic system (NNCS) that comprises of choline acetyltransferase (ChAT), choline transporter 1 (CHT1), vesicular acetylcholine transporter (VAChT), acetylcholinesterase (AChE) and type-2 muscarinic ACh receptors (M
METHODS
Ventricular samples from type-2 diabetic humans and db/db mice were used to measure the expression pattern of NNCS components (ChAT, CHT1, VAChT, AChE and M
RESULTS
Immunoblot analysis revealed alterations in the components of cardiac NNCS and GLUT-4 in the type-2 diabetic human and db/db mouse hearts. Interestingly, the dysregulation of cardiac NNCS was followed by the downregulation of GLUT-4 in the db/db mouse heart. Db/db-ChAT-tg mice exhibited preserved cardiac and vascular function in comparison to db/db mice. The improved function was associated with increased cardiac ACh and glucose content, sustained angiogenesis and reduced fibrosis. These beneficial effects were associated with upregulation of the PI3K/Akt/HIF1α signaling pathway, and increased expression of its downstream targets-GLUT-4 and VEGF-A.
CONCLUSION
We provide the first evidence for dysregulation of the cardiac NNCS in DHD. Increased cardiac ACh is beneficial and a potential new therapeutic strategy to prevent or delay the development of DHD.
Identifiants
pubmed: 33618724
doi: 10.1186/s12933-021-01231-8
pii: 10.1186/s12933-021-01231-8
pmc: PMC7898760
doi:
Substances chimiques
CHRM2 protein, human
0
CHT1 protein, mouse
0
GPI-Linked Proteins
0
Glucose Transporter Type 4
0
Membrane Transport Proteins
0
Receptor, Muscarinic M2
0
SLC18A3 protein, human
0
SLC2A4 protein, human
0
SLC5A7 protein, human
0
Slc18a3 protein, mouse
0
Slc2a4 protein, mouse
0
Symporters
0
Vesicular Acetylcholine Transport Proteins
0
Choline O-Acetyltransferase
EC 2.3.1.6
ACHE protein, human
EC 3.1.1.7
Acetylcholinesterase
EC 3.1.1.7
Ache protein, mouse
EC 3.1.1.7
Glucose
IY9XDZ35W2
Acetylcholine
N9YNS0M02X
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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