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Diabetes. 2014 Jun;63(6):2097-113. doi: 10.2337/db12-1459. Epub 2014 Jan 23.

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

Author information

  • 1Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
  • 2Departments of Neurology and Physiology, Medical College of Wisconsin, Milwaukee, WIDepartment of Medicine, Tufts University School of Medicine, Boston, MA.
  • 3Department of Neuroscience, Tufts University School of Medicine, Boston, MA.
  • 4Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
  • 5Department of Biochemistry & Molecular Biology, Louisiana State University School of Medicine, New Orleans, LA.
  • 6Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MADepartment of Medicine, Tufts University School of Medicine, Boston, MA.
  • 7Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA jgalper@tuftsmedicalcenter.org hpark@tuftsmedicalcenter.org.
  • 8Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MADepartment of Medicine, Tufts University School of Medicine, Boston, MA jgalper@tuftsmedicalcenter.org hpark@tuftsmedicalcenter.org.

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.

© 2014 by the American Diabetes Association.

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