Cardiomyocyte-specific deletion of GSK-3ß leads to cardiac dysfunction in a diet induced obesity model.
Int J Cardiol
; 259: 145-152, 2018 05 15.
Article
em En
| 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.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Deleção de Genes
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Miócitos Cardíacos
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Modelos Animais de Doenças
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Dieta Hiperlipídica
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Glicogênio Sintase Quinase 3 beta
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Obesidade
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article