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


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-3? (GSK3?) 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 GSK3? inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and IKACh, whereas a dominant-active GSK3? mutant decreased SREBP-1 and GIRK4 expression. In Akita mice treated with GSK3? 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 GSK3? activity in the type 1 diabetic heart plays a critical role in parasympathetic dysfunction through an effect on SREBP-1, supporting GSK3? as a new therapeutic target for diabetic autonomic neuropathy.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC4030105 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Zhang Yali Y   Welzig Charles M CM   Picard Kristen L KL   Du Chuang C   Wang Bo B   Pan Jen Q JQ   Kyriakis John M JM   Aronovitz Mark J MJ   Claycomb William C WC   Blanton Robert M RM   Park Ho-Jin HJ   Galper Jonas B JB  

Diabetes 20140123 6


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  ...[more]

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