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Glycogen Synthase Kinase-3β Inhibition Ameliorates Cardiac Parasympathetic Dysfunction in Type 1 Diabetic Akita Mice.
- Source :
- Diabetes; Jun2014, Vol. 63 Issue 6, p2097-2113, 17p, 8 Graphs
- Publication Year :
- 2014
-
Abstract
- Decreased heart rate variability (HRV) is a major risk factor for sudden death and cardiovascular disease. We previously demonstrated that parasympathetic dysfunction in the heart of the Akita type 1 diabetic mouse was due to a decrease in the level of the sterol response element-binding protein (SREBP-1). Here we demonstrate that hyperactivity of glycogen synthase kinase-3β (GSK3β) in the atrium of the Akita mouse results in decreased SREBP-1, attenuation of parasympathetic modulation of heart rate, measured as a decrease in the high-frequency (HF) fraction of HRV in the presence of propranolol, and a decrease in expression of the G-protein coupled inward rectifying K<superscript>+</superscript> (GIRK4) subunit of the acetylcholine (ACh)-activated inward-rectifying K<superscript>+</superscript> channel (I<subscript>KACh</subscript>), the ion channel that mediates the heart rate response to parasympathetic stimulation. Treatment of atrial myocytes with the GSK3β inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and I<subscript>KACh</subscript>, whereas a dominant-active GSK3β mutant decreased SREBP-1 and GIRK4 expression. In Akita mice treated with GSK3β inhibitors Li<superscript>+</superscript> and/or CHIR-99021, Li<superscript>+</superscript> increased I<subscript>KACh</subscript>, and Li<superscript>+</superscript> and CHIR-99021 both partially reversed the decrease in HF fraction while increasing GIRK4 and SREBP-1 expression. These data support the conclusion that increased GSK3β activity in the type 1 diabetic heart plays a critical role in parasympathetic dysfunction through an effect on SREBP-1, supporting GSK3β as a new therapeutic target for diabetic autonomic neuropathy. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 63
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 96165202
- Full Text :
- https://doi.org/10.2337/db12-1459