Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy via the TGF-β–Smad3 Pathway

Wang, Yinhui; Yu, Kun; Zhao, Chengcheng; Zhou, Ling; Cheng, Jia; Wang, Dao Wen; Zhao, Chunxia

doi:10.3389/fphar.2021.683335

Cited by 14 publications

(10 citation statements)

References 40 publications

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“…Myocardial fibrosis is an important pathological feature of DCM. We also confirmed that fibrosis plays a role in the development of diabetic cardiomyopathy, as evidenced by the accumulation of collagen in the myocardial interstitial and perivascular region in the heart tissues of DCM rats, as well as the increase in transcription and protein expression of Col1, Col3, α-SMA, and TGF-β1 both in vivo and in vitro , findings that were in line with previous studies ( Huynh et al, 2014 ; Wang Y. H. et al, 2021b ). The abovementioned effects were significantly attenuated with NOX1 inhibition, and further enhanced with NOX1 overexpression.…”

Section: Discussionsupporting

confidence: 92%

NOX1 promotes myocardial fibrosis and cardiac dysfunction via activating the TLR2/NF-κB pathway in diabetic cardiomyopathy

Zhang

Li²,

Wang³

et al. 2022

Front. Pharmacol.

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Diabetic cardiomyopathy (DCM) is a prevalent complication in patients with diabetes, resulting in high morbidity and mortality. However, the molecular mechanisms of diabetic cardiomyopathy have yet to be fully elucidated. In this study, we investigated a novel target, NOX1, an isoform of superoxide-producing NADPH oxidase with key functional involvement in the pathophysiology of DCM. The DCM rat model was established by a high-fat diet combined with streptozotocin injections. DCM rats elicited myocardial fibrosis exacerbation, which was accompanied by a marked elevation of NOX1 expression in cardiac tissue. In particular, a specific NOX1 inhibitor, ML171, effectively decreased myocardial fibrosis and protected against cardiac dysfunction in DCM rats. Rat neonatal cardiac fibroblasts were incubated with high glucose (HG, 33 mM) as an in vitro model of DCM. We also observed that the expression of NOX1 was upregulated in HG-cultured cardiac fibroblasts. Silencing of NOX1 was found to attenuate myocardial fibrosis and oxidative stress in HG-induced cardiac fibroblasts. Furthermore, the upregulation of NOX1 by hyperglycemia induced activation of the TLR2/NF-κB pathway both in vitro and in vivo, whereas these effects were significantly attenuated with NOX1 gene silencing and further enhanced with NOX1 gene overexpression. In summary, we demonstrated that NOX1 induced activation of the TLR2/NF-κB pathway and increased reactive oxygen species production accumulation, which ultimately increased myocardial fibrosis and deteriorated cardiac function in diabetic cardiomyopathy. Our study revealed that NOX1 was a potential therapeutic target for DCM.

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Section: Discussionsupporting

confidence: 92%

NOX1 promotes myocardial fibrosis and cardiac dysfunction via activating the TLR2/NF-κB pathway in diabetic cardiomyopathy

Zhang

Li²,

Wang³

et al. 2022

Front. Pharmacol.

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“…Our data also support an observation in a randomized control trial and other rat models of DCM in which ALA administration prevented an increase in heart mitochondrial ROS production and effectively enhanced SOD activity and GSH content of myocardial mitochondria as well as decreased collagen deposition and TGF-β1 and mitochondria-dependent cardiac apoptosis ( Midaoui et al, 2003 ; Li et al, 2009 ; Lee J. E. et al, 2012 ; Hegazy et al, 2013 ). ROS promotes development of cardiac fibrosis in DCM by upregulating TGF-β1 and its downstream proteins Smad2 and 3 ( Purnomo et al, 2013 ; Wang et al, 2019 ; Wang et al, 2021 ) as was also observed in the present study. Moreover, Micheloudes et al (2011) reported that overexpression of TGF-β1 resulted in increased ROS-induced oxidative stress via increased expression of NADPH oxidase 4 (NOX4; a major modulator of ROS-related fibrosis) and decreased the activity of the mitochondrial antioxidant manganese-dependent superoxide dismutase (MnSOD).…”

Section: Discussionsupporting

confidence: 88%

“…Among these mechanisms, ROS-induced oxidative stress has received significant experimental attention as the unifying contributing factor in DCM development and progression ( Kakkar et al, 1995 ; Ghosh et al, 2004 ; Hamblin et al, 2007 ; Singh et al, 2008 ; Das et al, 2012 ; Tocchetti et al, 2015 ). Burgeoning evidence also shows that ROS-induced oxidative stress contributes to development of cardiac fibrosis in DCM by upregulating the expression of transforming growth factor-beta 1 (TGF-β1; a central mediator of cardiac fibrosis) ( Purnomo et al, 2013 ; Zhang et al, 2018; Wang et al, 2019 ; Wang et al, 2021 ). TGF-β1 induces remodeling and fibrosis in cardiac tissue and other tissues through activation of its downstream effector proteins referred to as Smads, which include Smad 2/3, Smad 4 and other Smads.…”

Section: Introductionmentioning

confidence: 99%

Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway

et al. 2022

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Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM.Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods.Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1β, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-β1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001).Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-β1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.

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“… 45 A recent study found that FST could downregulate the Akt pathway in cardiocytes. 46 Thus, we assumed that mTOR was a key factor underlying how FST regulated lipid synthesis. We found that FST was a negative regulator of Akt and mTOR signaling in hepatic lipid synthesis.…”

Section: Discussionmentioning

confidence: 99%

Follistatin Alleviates Hepatic Steatosis in NAFLD via the mTOR Dependent Pathway

Tong¹,

Cong²,

Jia³

et al. 2022

DMSO

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Purpose In this study, we aimed to investigate the effect of follistatin (FST) on hepatic steatosis in NAFLD and the underlying mechanism, which has rarely been reported before. Methods Liver samples from NAFLD patients and normal liver samples (from liver donors) were collected to investigate hepatic FST expression in humans. Additionally, human liver cells (LO2) were treated with free fatty acid (FFA) to induce lipid accumulation. Furthermore, lentivirus with FST overexpression or knockdown vectors were used to generate stable cell lines, which were subsequently treated with FFA or FFA and rapamycin. In the animal experiments, male C57BL/6J mice were fed with a high-fat diet (HFD) to induce NAFLD, after which the adeno-associated virus (AAV) gene vectors for FST overexpression were administered. In both cell culture and mice, we evaluated morphological changes and the protein expression of sterol regulatory element-binding protein1 (SREBP1), acetyl-CoA carboxylase1 (ACC1), carbohydrate-responsive element-binding protein (ChREBP), fatty acid synthase (FASN), and Akt/mTOR signaling. The body weight and serum parameters of the mice were also measured. Results Hepatic FST expression level was higher in NAFLD patients compared to normal samples. In LO2 cells, FST overexpression alleviated lipid accumulation and lipogenesis, whereas FST knockdown aggravated hepatic steatosis. FST could regulate Akt/mTOR signaling, and the mTOR inhibitor rapamycin abolished the effect of FST knockdown on hepatic de novo lipogenesis (DNL). Furthermore, FST expression was increased in HFD mice compared to the corresponding controls. FST overexpression in mice reduced body weight gain, hyperlipidemia, hepatic DNL, and suppressed Akt/mTOR signaling. Conclusion Hepatic FST expression increases in NAFLD and plays a protective role in hepatic steatosis. FST overexpression gene therapy alleviates hepatic steatosis via the mTOR pathway.Therefore, gene therapy for FST is a promising treatment in NAFLD.

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Follistatin Attenuates Myocardial Fibrosis in Diabetic Cardiomyopathy via the TGF-β–Smad3 Pathway

Cited by 14 publications

References 40 publications

NOX1 promotes myocardial fibrosis and cardiac dysfunction via activating the TLR2/NF-κB pathway in diabetic cardiomyopathy

NOX1 promotes myocardial fibrosis and cardiac dysfunction via activating the TLR2/NF-κB pathway in diabetic cardiomyopathy

Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway

Follistatin Alleviates Hepatic Steatosis in NAFLD via the mTOR Dependent Pathway

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