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Glycogen synthase kinase-3β inhibition ameliorates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice
Yali Zhang1, Charles M Welzig2, Kristen L Picard1
1Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
Insights
Glycogen synthase kinase-3β (GSK3β) hyperactivity in type 1 diabetes impairs heart rate variability by reducing SREBP-1 and GIRK4. Inhibiting GSK3β improves parasympathetic function and offers a therapeutic target for diabetic autonomic neuropathy.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Diabetology
Background:
- Decreased heart rate variability (HRV) is a significant risk factor for sudden cardiac death and cardiovascular disease.
- Parasympathetic dysfunction in the type 1 diabetic Akita mouse heart is linked to reduced sterol response element-binding protein (SREBP-1).
Purpose of the Study:
- To investigate the role of glycogen synthase kinase-3β (GSK3β) hyperactivity in atrial parasympathetic dysfunction in the Akita mouse model of type 1 diabetes.
- To determine if GSK3β influences SREBP-1 levels and the expression of the G-protein coupled inward rectifying K(+) (GIRK4) subunit of the inward-rectifying K(+) channel (IKACh).
Main Methods:
- Assessed GSK3β activity, SREBP-1 levels, and GIRK4 expression in atrial myocytes and hearts of Akita mice.
- Utilized GSK3β inhibitors (Kenpaullone, Li+, CHIR-99021) and a dominant-active GSK3β mutant in cellular and animal models.
- Measured heart rate modulation via the high-frequency (HF) fraction of HRV and IKACh activity.
Main Results:
- Hyperactive GSK3β in Akita mouse atria decreased SREBP-1, attenuated parasympathetic heart rate modulation (reduced HF fraction), and decreased GIRK4 expression.
- GSK3β inhibition increased SREBP-1 and GIRK4 expression in atrial myocytes.
- Treatment of Akita mice with GSK3β inhibitors partially reversed reduced HF fraction and increased GIRK4 and SREBP-1 expression.
Conclusions:
- Increased GSK3β activity in the type 1 diabetic heart contributes to parasympathetic dysfunction via SREBP-1.
- GSK3β is identified as a potential therapeutic target for diabetic autonomic neuropathy.
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(+) (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.
