Glycogen synthase kinase-3β inhibition ameliorates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice.
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.
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
Yali
Y
Zhang
Departments of Neurology and Physiology, Medical College of Wisconsin, Milwaukee, WIDepartment of Medicine, Tufts University School of Medicine, Boston, MA.
Charles M
CM
Welzig
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
Kristen L
KL
Picard
Department of Neuroscience, Tufts University School of Medicine, Boston, MA.
Chuang
C
Du
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
Bo
B
Wang
Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
Jen Q
JQ
Pan
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
John M
JM
Kyriakis
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA.
Mark J
MJ
Aronovitz
Department of Biochemistry & Molecular Biology, Louisiana State University School of Medicine, New Orleans, LA.
William C
WC
Claycomb
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MADepartment of Medicine, Tufts University School of Medicine, Boston, MA.
Robert M
RM
Blanton
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA jgalper@tuftsmedicalcenter.org hpark@tuftsmedicalcenter.org.
Ho-Jin
HJ
Park
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MADepartment of Medicine, Tufts University School of Medicine, Boston, MA jgalper@tuftsmedicalcenter.org hpark@tuftsmedicalcenter.org.
Jonas B
JB
Galper
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000378:metabolism* / Q000503:physiopathology; D004562:Electrocardiography; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006325:Heart Atria / Q000503:physiopathology; D006339:Heart Rate; D051379:Mice; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010275:Parasympathetic Nervous System / Q000378:metabolism* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D051780:Sterol Regulatory Element Binding Protein 1 / Q000187:drug effects* / Q000378:metabolism
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484273:Kcnj5 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3