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

Gupte, Manisha; Tumuluru, Samvruta; Sui, Jennifer Y.; Singh, Anand Prakash; Umbarkar, Prachi; Parikh, Shan; Ahmad, Firdos; Zhang, Qinkun; Force, Thomas; Lal, Hind

doi:10.1016/j.ijcard.2018.01.013

Cited by 24 publications

(26 citation statements)

References 42 publications

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“…This causes an activation of the signal transduction molecule disheveled (Dvl) which, in turn, inhibits the (GSK-3β), the expression level of β-catenin increased. However, we found that the expression of p-GSK-3β was different from the results of previous studies (Gupte et al, 2018), which may be related to the time stage after myocardial infarction (Lal et al, 2014) or likely related different MI areas, such as MI and non-MI areas or maybe lcz696 likely regulating β-catenin and GSK-3β through two independent pathways, this will encourage us to explore further.…”

Section: Discussioncontrasting

confidence: 65%

Lcz696 Alleviates Myocardial Fibrosis After Myocardial Infarction Through the sFRP-1/Wnt/β-Catenin Signaling Pathway

et al. 2021

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Background: Lcz696 (ARNI, angiotensin receptor–neprilysin inhibitor; sacubitril/valsartan) shows an inhibitory effect on fibrosis after myocardial infarction (MI). However, the underlying signaling mechanisms are poorly understood. The Wnt/β-catenin signaling pathway is activated after MI and participates in the process of myocardial fibrosis. Here, we aimed to assess the efficacy of ARNI for alleviating myocardial fibrosis after MI and hypothesized that ARNI alleviates myocardial fibrosis by inhibiting the Wnt/β-catenin signaling pathway and overexpressing sFRP-1, an inhibitor of the Wnt/β-catenin signaling pathway.Methods: Mice randomized at 1 week post-MI were administered lcz696 (60 mg/kg, n = 21), valsartan (30 mg/kg, n = 19), or corn oil (n = 13) orally for 4 weeks, while the sham-operated group received vehicle (corn oil, n = 19). Cardiac function and extent of myocardial fibrosis were measured. Western blotting and quantitative real-time polymerase chain reaction were used to detect the expression of Wnt/β-catenin pathway-related proteins. Furthermore, primary myocardial fibroblasts were stimulated with angiotensin II (Ang II) and cultured with lcz696 and the sFRP-1 inhibitor way316606 to detect the expression of Wnt/β-catenin pathway proteins.Results: Both lcz696 and valsartan alleviated myocardial fibrosis and improved cardiac function, but lcz696 had superior efficiency compared to valsartan. Furthermore, β-catenin expression was inhibited and sFRP-1 was overexpressed after drug treatment, which could be significantly improved by lcz696 in mice. In addition, lcz696 inhibited β-catenin expression in AngII-stimulated myocardial fibroblasts, and β-catenin expression increased after the inhibition of sFRP-1.Conclusion: ARNI alleviated cardiac fibrosis and cardiac remodeling by inhibiting the Wnt/β-catenin signaling pathway. In addition, ARNI can lead to overexpression of sFRP-1, which is an inhibitor of the Wnt/β-catenin signaling pathway. These results indicate a new therapeutic target of ARNI to improve myocardial fibrosis and prevent myocardial remodeling.

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Section: Discussioncontrasting

confidence: 65%

Lcz696 Alleviates Myocardial Fibrosis After Myocardial Infarction Through the sFRP-1/Wnt/β-Catenin Signaling Pathway

et al. 2021

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“…Heart weight did not differ between groups (p>0.05) ( Table 1). However, Gupte et al (28) found a higher absolute heart weight in rats that received a lipid-rich diet for 385 days, suggesting that, in the long term, the hyperlipidic diet can cause changes in the weight of this organ.…”

Section: Resultsmentioning

confidence: 99%

Heart structure, serum cholesterol, and adiposity of rats treated with a hypercaloric diet: effectiveness of Citrus sinensis (L.) Osbeck and swimming

et al. 2020

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This study evaluated the effects of the herbal medicine red orange (Citrus sinensis (L.) Osbeck) and swimming for 84 days on the animal, heart, and abdominal fat weight and the histomorphometric aspects of heart and total cholesterol of Wistar rats. The rats were divided into seven experimental groups of 12 animals each, consisting of a normocaloric diet (Dn), hypercaloric diet (Dh), normocaloric diet and herbal medicine (DnH), hypercaloric diet and herbal medicine (DhH), normocaloric diet and swimming (DnS), hypercaloric diet and swimming (DhS), and hypercaloric diet, swimming, and herbal medicine (DhSH). The data were analyzed statistically by the Tukey test and considered significant when p<0.05. Groups treated with the normocaloric diet had lower abdominal fat weight. The normocaloric diet and herbal medicine (DnH) provided the smallest thickness of the right ventricle. The hypercaloric diet (Dh) reduced the number of cardiomyocytes and the perimeter of cardiac muscle fibers. Swimming and the red orange extract acted synergistically by reducing the deleterious effects of the hypercaloric diet and increasing the thickness of the cardiac chambers and the number of cardiomyocytes. Only the supplementation with the red orange extract did not reduce abdominal fat in rats treated with a hypercaloric diet. Therefore, red orange alone did not promote beneficial changes in the studied data, but its association with swimming increased the number of cardiomyocytes and thickness of muscle fibers, which could contribute to preventing cardiovascular diseases and maintaining health, as well as the regular swimming and a normocaloric diet, which provided less adiposity.

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“…000664, The Jackson Laboratory) to generate Myh6-Cre +/– . A well-established TAM chow diet protocol was used to induce the CM-specific expression of Cre recombinase, as we previously reported 26, 27. Briefly, at 10 weeks of age, when physiological development is largely complete, all male mice were placed on a TAM chow diet (400 mg/kg, TD.130859, Harlan Sprague-Dawley, Indianapolis, Indiana) for 2 weeks followed by regular chow for an additional 4 weeks (to allow the clearance of TAM from the mice) (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

Cardiomyocyte SMAD4-Dependent TGF-β Signaling is Essential to Maintain Adult Heart Homeostasis

Umbarkar

Singh

Gupte

et al. 2019

JACC: Basic to Translational Science

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

Abstract: In summary, these results suggest that cardiac GSK-3β is crucial to protect against obesity-induced adverse ventricular remodeling and cardiac dysfunction.

Cited by 24 publications

References 42 publications

Lcz696 Alleviates Myocardial Fibrosis After Myocardial Infarction Through the sFRP-1/Wnt/β-Catenin Signaling Pathway

Lcz696 Alleviates Myocardial Fibrosis After Myocardial Infarction Through the sFRP-1/Wnt/β-Catenin Signaling Pathway

Heart structure, serum cholesterol, and adiposity of rats treated with a hypercaloric diet: effectiveness of Citrus sinensis (L.) Osbeck and swimming

Cardiomyocyte SMAD4-Dependent TGF-β Signaling is Essential to Maintain Adult Heart Homeostasis

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