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Int J Cardiol ; 259: 145-152, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29398139

ABSTRACT

BACKGROUND AND RATIONALE: Obesity, an independent risk factor for the development of myocardial diseases is a growing healthcare problem worldwide. It's well established that GSK-3ß is critical to cardiac pathophysiology. However, the role cardiomyocyte (CM) GSK-3ß in diet-induced cardiac dysfunction is unknown. METHODS: CM-specific GSK-3ß knockout (CM-GSK-3ß-KO) and littermate controls (WT) mice were fed either a control diet (CD) or high-fat diet (HFD) for 55weeks. Cardiac function was assessed by transthoracic echocardiography. RESULTS: At baseline, body weights and cardiac function were comparable between the WT and CM-GSK-3ß-KOs. However, HFD-fed CM-GSK-3ß-KO mice developed severe cardiac dysfunction. Consistently, both heart weight/tibia length and lung weight/tibia length were significantly elevated in the HFD-fed CM-GSK-3ß-KO mice. The impaired cardiac function and adverse ventricular remodeling in the CM-GSK-3ß-KOs were independent of body weight or the lean/fat mass composition as HFD-fed CM-GSK-3ß-KO and controls demonstrated comparable body weight and body masses. At the molecular level, on a CD, CM-GSK-3α compensated for the loss of CM-GSK-3ß, as evident by significantly reduced GSK-3αs21 phosphorylation (activation) resulting in a preserved canonical ß-catenin ubiquitination pathway and cardiac function. However, this protective compensatory mechanism is lost with HFD, leading to excessive accumulation of ß-catenin in HFD-fed CM-GSK-3ß-KO hearts, resulting in adverse ventricular remodeling and cardiac dysfunction. CONCLUSION: In summary, these results suggest that cardiac GSK-3ß is crucial to protect against obesity-induced adverse ventricular remodeling and cardiac dysfunction.


Subject(s)
Diet, High-Fat/adverse effects , Disease Models, Animal , Gene Deletion , Glycogen Synthase Kinase 3 beta/deficiency , Myocytes, Cardiac/enzymology , Obesity/enzymology , Animals , Glycogen Synthase Kinase 3 beta/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myocytes, Cardiac/pathology , Obesity/genetics , Obesity/pathology
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