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Cardiomyocyte-specific deletion of GSK-3? leads to cardiac dysfunction in a diet induced obesity model.

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-3? is critical to cardiac pathophysiology. However, the role cardiomyocyte (CM) GSK-3? in diet-induced cardiac dysfunction is unknown. METHODS:CM-specific GSK-3? knockout (CM-GSK-3?-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-3?-KOs. However, HFD-fed CM-GSK-3?-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-3?-KO mice. The impaired cardiac function and adverse ventricular remodeling in the CM-GSK-3?-KOs were independent of body weight or the lean/fat mass composition as HFD-fed CM-GSK-3?-KO and controls demonstrated comparable body weight and body masses. At the molecular level, on a CD, CM-GSK-3? compensated for the loss of CM-GSK-3?, as evident by significantly reduced GSK-3?s21 phosphorylation (activation) resulting in a preserved canonical ?-catenin ubiquitination pathway and cardiac function. However, this protective compensatory mechanism is lost with HFD, leading to excessive accumulation of ?-catenin in HFD-fed CM-GSK-3?-KO hearts, resulting in adverse ventricular remodeling and cardiac dysfunction. CONCLUSION:In summary, these results suggest that cardiac GSK-3? is crucial to protect against obesity-induced adverse ventricular remodeling and cardiac dysfunction.

SUBMITTER: Gupte M

PROVIDER: S-EPMC5869114 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Cardiomyocyte-specific deletion of GSK-3β leads to cardiac dysfunction in a diet induced obesity model.

Gupte Manisha M Tumuluru Samvruta S Sui Jennifer Y JY Singh Anand Prakash AP Umbarkar Prachi P Parikh Shan S SS Ahmad Firdos F Zhang Qinkun Q Force Thomas T Lal Hind H

International journal of cardiology 20180203

<h4>Background and rationale</h4>Obesity, an independent risk factor for the development of myocardial diseases is a growing healthcare problem worldwide. It's well established that GSK-3β is critical to cardiac pathophysiology. However, the role cardiomyocyte (CM) GSK-3β in diet-induced cardiac dysfunction is unknown.<h4>Methods</h4>CM-specific GSK-3β knockout (CM-GSK-3β-KO) and littermate controls (WT) mice were fed either a control diet (CD) or high-fat diet (HFD) for 55weeks. Cardiac functio ...[more]

PMID: 29398139

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Project description:BackgroundEnvironmental factors are well-known causes of diseases. However, aside from a handful of risk indicators, genes' encoding susceptibility to chronic illnesses and their associated environmental triggers are largely unknown. In this era of increasingly rich diets, such genetic predispositions would be immensely helpful from a public health perspective. The novel transgenic mouse model with liver-specific NG37 overexpression characterized in this article identifies the diet-dependent function of NG37 in the pathogenesis of fatty liver disease and cardiac arrhythmia.ResultsThe liver-specific NG37 overexpression transgenic mouse model described here was generated using the Alb-SV40 polyA expression plasmid backbone. NG37 cDNA under control of the albumin promoter for liver-specific expression was fused with a 5' terminal M2 FLAG sequence and a SV40 early region transcription terminator/polyadenylation site attached at the 3'-UTR. These NG37 transgenic mice developed normally and were physiologically normal on a standard diet. However, in comparison to non-transgenic (nTG) litter mates, these mice develop dramatic phenotypes within 12-18 days of starting a high-fat diet: (i) increased body weight (28.5?±?12.3 g), (ii) increased liver weight (87.4?±?35.7 mg), (iii) increased heart weight (140?±?38.4 mg), and (iv) cardiac arrhythmia. The enlarged livers of high-fat diet NG37 transgenic mice was histologically similar to human fatty liver disease and contained Maltese cross birefringent active depositions in hepatocytes that are indicative of fatty liver disease. We also confirmed via X-ray diffraction the steatotic vesicles in the diseased hepatocytes of our high-fat diet NG37 mice was composed of cholesteryl derivatives also found in human fatty liver disease. In addition to cardiac enlargement, NG37 transgenic mice on high-fat diet also exhibited highly irregular bradycardia not present in either high-fat diet nTG littermates or normal-diet transgenic litter mates.ConclusionsThe dramatic high-fat diet-dependent symptoms (increased body weight, cardiac enlargement, fatty liver, and cardiac arrhythmias) characterized in our liver-specific NG37 overexpression mouse model identifies NG37 as a gene encoding latent lipid metabolism pathology induced only in the presence of an environmental factor relevant to human health: high-fat diet.

Project description:RationaleThe Hippo pathway plays an important role in determining organ size through regulation of cell proliferation and apoptosis. Hippo inactivation and consequent activation of YAP (Yes-associated protein), a transcription cofactor, have been proposed as a strategy to promote myocardial regeneration after myocardial infarction. However, the long-term effects of Hippo deficiency on cardiac function under stress remain unknown.ObjectiveWe investigated the long-term effect of Hippo deficiency on cardiac function in the presence of pressure overload (PO).Methods and resultsWe used mice with cardiac-specific homozygous knockout of WW45 (WW45cKO), in which activation of Mst1 (Mammalian sterile 20-like 1) and Lats2 (large tumor suppressor kinase 2), the upstream kinases of the Hippo pathway, is effectively suppressed because of the absence of the scaffolding protein. We used male mice at 3 to 4 month of age in all animal experiments. We subjected WW45cKO mice to transverse aortic constriction for up to 12 weeks. WW45cKO mice exhibited higher levels of nuclear YAP in cardiomyocytes during PO. Unexpectedly, the progression of cardiac dysfunction induced by PO was exacerbated in WW45cKO mice, despite decreased apoptosis and activated cardiomyocyte cell cycle reentry. WW45cKO mice exhibited cardiomyocyte sarcomere disarray and upregulation of TEAD1 (transcriptional enhancer factor) target genes involved in cardiomyocyte dedifferentiation during PO. Genetic and pharmacological inactivation of the YAP-TEAD1 pathway reduced the PO-induced cardiac dysfunction in WW45cKO mice and attenuated cardiomyocyte dedifferentiation. Furthermore, the YAP-TEAD1 pathway upregulated OSM (oncostatin M) and OSM receptors, which played an essential role in mediating cardiomyocyte dedifferentiation. OSM also upregulated YAP and TEAD1 and promoted cardiomyocyte dedifferentiation, indicating the existence of a positive feedback mechanism consisting of YAP, TEAD1, and OSM.ConclusionsAlthough activation of YAP promotes cardiomyocyte regeneration after cardiac injury, it induces cardiomyocyte dedifferentiation and heart failure in the long-term in the presence of PO through activation of the YAP-TEAD1-OSM positive feedback mechanism.

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Cardiomyocyte-specific deletion of GSK-3? leads to cardiac dysfunction in a diet induced obesity model.

Publications

Cardiomyocyte-specific deletion of GSK-3β leads to cardiac dysfunction in a diet induced obesity model.

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