Glycogen Synthase Kinase-3β Inhibition Ameliorates Cardiac Parasympathetic Dysfunction in Type 1 Diabetic Akita Mice
- Yali Zhang1,
- Charles M. Welzig2,3,
- Kristen L. Picard1,
- Chuang Du4,
- Bo Wang1,
- Jen Q. Pan5,
- John M. Kyriakis1,
- Mark J. Aronovitz1,
- William C. Claycomb6,
- Robert M. Blanton1,3,
- Ho-Jin Park1⇑ and
- Jonas B. Galper1,3⇑
- 1Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA
- 2Departments of Neurology and Physiology, Medical College of Wisconsin, Milwaukee, WI
- 3Department of Medicine, Tufts University School of Medicine, Boston, MA
- 4Department of Neuroscience, Tufts University School of Medicine, Boston, MA
- 5Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA
- 6Department of Biochemistry & Molecular Biology, Louisiana State University School of Medicine, New Orleans, LA
- Corresponding authors: Jonas B. Galper, , and Ho-Jin Park, .
Y.Z. and C.M.W. contributed equally to this work.
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1459/-/DC1.
See accompanying article, p. 1847.
- Received October 24, 2012.
- Accepted January 14, 2014.
- © 2014 by the American Diabetes Association.
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