Glycogen Synthase Kinase-3β 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-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.

Glycolysis regulated transglutaminase 2 activation in cardiopulmonary fibrogenic remodeling

“…15 To further examine the role of aberrant glucose metabolism and TG2 induction, we analyzed the terminal glycolytic enzyme PKM2 expression and TG2 activity and expression levels in this chronic type 1 diabetic mouse model with hyperglycemia. 15 To further examine the role of aberrant glucose metabolism and TG2 induction, we analyzed the terminal glycolytic enzyme PKM2 expression and TG2 activity and expression levels in this chronic type 1 diabetic mouse model with hyperglycemia.…”

“…Previous studies reported that Akita mice spontaneously develop diabetes associated with significantly increased blood glucose levels. 15 To further examine the role of aberrant glucose metabolism and TG2 induction, we analyzed the terminal glycolytic enzyme PKM2 expression and TG2 activity and expression levels in this chronic type 1 diabetic mouse model with hyperglycemia. We found significantly elevated PKM2 expression levels in lung and LV tissues while the increase in PKM2 expression in RVs was only minimal in the hyperglycemic Akita mice compared to age-matched WT mice.…”

“…8 Because of an established role for stimulation of anaerobic glycolysis by exposure to hypoxia, 9 we pursued other physiological experiments where glycolysis is enhanced to determine if glycolysis itself may be stimulatory for TG2 and fibrotic alterations of tissues. 15 Glycolysis is stimulated by hypoxia and is also upregulated in the presence of oxygen as in tumor biology where it has been referred to as the Warburg effect (aerobic glycolysis). We attempted to identify the influence of tissue pressure overload on TG2 expression and activity in LVs of the TAC experimental mouse model.…”

Resveratrol Improves Cardiac Functions of the Diabetic Cardiomyopathy Rats Via Modulation of AMP-Activated Protein Kinase and the Phosphorylated Glycogen Synthase Kinase-3(3

“…Elevated levels of GSK-3 β S9 has been linked to improved cardiac autonomic dysfunction, reduced mitochondrial injury, improved cardiac survival, structure and function [18] . In the diabetic cardiomyopathy, the expression of post-insulin receptor signaling was extremely reduced.…”

Complexity of Impaired Parasympathetic Heart Rate Regulation in Diabetes

“…In this issue, Zhang et al (9) conducted such a study in diabetic Akita mice. In these animals, a point mutation in the insulin 2 gene leads to production of a misfolded protein, pancreatic b-cell destruction, and a metabolic phenotype resembling type 1 diabetes.…”