NDLI: Activation of the cardiac non-neuronal cholinergic system prevents the development of diabetes-associated cardiovascular complications

Content Provider	Springer Nature : BioMed Central
Author	Saw, Eng Leng Pearson, James T. Schwenke, Daryl O. Munasinghe, Pujika Emani Tsuchimochi, Hirotsugu Rawal, Shruti Coffey, Sean Davis, Philip Bunton, Richard Van Hout, Isabelle Kai, Yuko Williams, Michael J. A. Kakinuma, Yoshihiko Fronius, Martin Katare, Rajesh
Abstract	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 (M2AChR) to synthesize, release, degrade ACh as well as for ACh to transduce a signal. NNCS is linked to cardiac cell survival, angiogenesis and glucose metabolism. Impairment of these functions are hallmarks of diabetic heart disease (DHD). The role of the NNCS in DHD is unknown. The aim of this study was to examine the effect of diabetes on cardiac NNCS and determine if activation of cardiac NNCS is beneficial to the diabetic heart. 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 M2AChR) and glucose transporter-4 (GLUT-4) by western blot analysis. To determine the function of the cardiac NNCS in the diabetic heart, a db/db mouse model with cardiac-specific overexpression of ChAT gene was generated (db/db-ChAT-tg). Animals were followed up serially and samples collected at different time points for molecular and histological analysis of cardiac NNCS components and prosurvival and proangiogenic signaling pathways. 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.
Related Links	https://cardiab.biomedcentral.com/counter/pdf/10.1186/s12933-021-01231-8.pdf
Ending Page	16
Page Count	16
Starting Page	1
File Format	HTM / HTML
ISSN	14752840
DOI	10.1186/s12933-021-01231-8
Journal	Cardiovascular Diabetology
Issue Number	1
Volume Number	20
Language	English
Publisher	BioMed Central
Publisher Date	2021-02-22
Access Restriction	Open
Subject Keyword	Diabetes Angiology Cardiology Non-neuronal cholinergic system Acetylcholine Diabetic heart disease Glucose metabolism Angiogenesis
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine Internal Medicine Endocrinology, Diabetes and Metabolism
Journal Impact Factor	8.5/2023
5-Year Journal Impact Factor	8.9/2023

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