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Diabetes DOI:10.2337/db12-1459

Glycogen synthase kinase-3β inhibition ameliorates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice.

Publication TypeJournal Article
Year of Publication2014
AuthorsZhang, Y, Welzig, CM, Picard, KL, Du, C, Wang, B, Pan, JQ, Kyriakis, JM, Aronovitz, MJ, Claycomb, WC, Blanton, RM, Park, H-J, Galper, JB
Date Published2014 Jun
KeywordsAnimals, Blotting, Western, Cells, Cultured, Diabetes Mellitus, Type 1, Diabetic Neuropathies, Electrocardiography, G Protein-Coupled Inwardly-Rectifying Potassium Channels, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Heart Atria, Heart Rate, Mice, Mice, Mutant Strains, Myocytes, Cardiac, Parasympathetic Nervous System, Patch-Clamp Techniques, Sterol Regulatory Element Binding Protein 1

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(+) (GIRK4) subunit of the acetylcholine (ACh)-activated inward-rectifying K(+) channel (IKACh), 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 IKACh, whereas a dominant-active GSK3β mutant decreased SREBP-1 and GIRK4 expression. In Akita mice treated with GSK3β inhibitors Li(+) and/or CHIR-99021, Li(+) increased IKACh, and Li(+) 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.


Alternate JournalDiabetes
PubMed ID24458356
PubMed Central IDPMC4030105
Grant ListR21 DK079622 / DK / NIDDK NIH HHS / United States
R01 HL074876 / HL / NHLBI NIH HHS / United States
R21-DK-079622 / DK / NIDDK NIH HHS / United States
HL-074876 / HL / NHLBI NIH HHS / United States
P30 NS047243 / NS / NINDS NIH HHS / United States
P30-NS047243 / NS / NINDS NIH HHS / United States