Abstract
Objective Obesity causes a variety of metabolic alterations that may contribute to abnormalities of the cardiac structure and function (obesity cardiomyopathy). In previous works, we have shown that pentamethylquercetin (PMQ) significantly improved metabolic disorders in obese mice and it inhibited pressure overload-induced cardiac remodeling in mice. However, its potential benefit in obesity cardiomyopathy remains unclear. The aim of this study was to investigate the effects of PMQ on cardiac remodeling in obese mice. Methods We generated a monosodium glutamate-induced obese (MSG-IO) model in mice, which were treated with PMQ (5, 10, and 20 mg/kg) for 16 weeks consecutively. We examined the metabolic parameters and observed cardiac remodeling by performing cardiac echocardiography and Masson's staining. The expression levels of molecules associated with the endogenous antioxidant system, including the sestrins/kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway, were analyzed by western blotting and immunofluorescent staining. Results We found that PMQ treatment significantly ameliorated obesity phenotypes and improved metabolic disorders in MSG-IO mice. PMQ decreased the heart wall thickness and attenuated cardiac fibrosis. Further study revealed that the protective effects of PMQ might be mediated by promoting Keap1 degradation and augmenting sestrins expression and Nrf2 nuclear translocation. Conclusion Our findings indicated that PMQ ameliorated cardiac remodeling in obese mice by targeting the sestrins/Keap1/Nrf2 signaling pathway.
Highlights
Obesity can cause a variety of alterations that may predispose to changes in the cardiac morphology and ventricular function [1, 2]
Erefore, the present study investigated the protective effects of PMQ on cardiac remodeling in monosodium glutamate-induced obese (MSG-IO) mice and ascertained whether the protective effects of PMQ are associated with the sestrins/kelch-like ECH-associated protein 1 (Keap1)/Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway
We showed that PMQ could resist cardiac remodeling associated with obesity, which might be mediated by improving the metabolism disorders and enhancing the endogenous antioxidant system of the sestrins/ Keap1/Nrf2 signaling pathway. ese findings suggest the potential of sestrins as the key molecules and drug targets for obesity-related cardiac remodeling
Summary
Obesity can cause a variety of alterations that may predispose to changes in the cardiac morphology and ventricular function [1, 2]. Several mechanisms are associated with obesity cardiomyopathy, including inflammation and various neurohormonal and metabolic abnormalities. Oxidative stress, another important factor, plays a significant role in myocardial abnormalities related to obesity [3]. Genetic depletion of sestrins has been found to result in exacerbation of obesity-associated pathological disorders, including fat accumulation, insulin resistance, mitochondrial pathologies, and cardiac dysfunction, in multiple animal models, which could be relieved by treatments that suppress ROS signaling [4]. Current studies assessing the direct role of sestrins in cardiac pathophysiology are relatively limited. Our previous study showed that Sestrin participated in the cardiac remodeling process, and the pentamethylquercetin (PMQ) protective effect against cardiac remodeling induced by pressure overload was sestrin dependent [5]. Whether sestrins have a protective effect on obesity cardiomyopathy needs to be studied further
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