Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy

Yue, Yiyang; Meng, Ke; Pu, Yuejie; Zhang, Xiaoming

doi:10.1016/j.diabres.2017.08.018

Cited by 183 publications

(141 citation statements)

References 57 publications

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“…These findings are consistent with evidence that progressive obesity develops in ob/ ob and db/db mice at 6 months of age, but none of ob/ob mice have LVH at 2 months 2 . LVH is associated with fibrosis, which results in elevated dysferlin that functions in cardiac extracellular membrane repair, and TGF-β1 is www.nature.com/scientificreports www.nature.com/scientificreports/ increased in hyperglycemia in diabetic models 20,21 . Indeed, we found that soluble ST2, a fibrosis biomarker, is elevated in ob/ob mice at 25 weeks of age, which is consistent with findings reported from obese rats, in which serum ST2, collagen type 1, and profibrotic factors were elevated 22 .…”

Section: Discussionmentioning

confidence: 99%

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

Lee

Choi

et al. 2020

Sci Rep

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Leptin-deficient and leptin-resistant mice manifest obesity, insulin resistance, and left ventricular hypertrophy (LVH); however, LVH's mechanisms are not fully understood. Cardiac iron dysregulation has been recently implicated in cardiomyopathy. Here we investigated the protective effects of caloric restriction on cardiac remodeling in impaired leptin signaling obese mice. RNA-seq analysis was performed to assess the differential gene expressions in the heart of wild-type and ob/ob mice. In particular, to investigate the roles of caloric restriction on iron homeostasis-related gene expressions, 10-week-old ob/ob and db/db mice were assigned to ad libitum or calorie-restricted diets for 12 weeks. Male ob/ob mice exhibited LVH, cardiac inflammation, and oxidative stress. Using RNA-seq analysis, we identified that an iron uptake-associated gene, transferrin receptor, was upregulated in obese ob/ob mice with LVH. Caloric restriction attenuated myocyte hypertrophy, cardiac inflammation, fibrosis, and oxidative stress in ob/ob and db/db mice. Furthermore, we found that caloric restriction reversed iron homeostasis-related lipocalin 2, divalent metal transporter 1, transferrin receptor, ferritin, ferroportin, and hepcidin expressions in the heart of ob/ob and db/db mice. These findings demonstrate that the cardioprotective effects of caloric restriction result from the cellular regulation of iron homeostasis, thereby decreasing oxidative stress, inflammation, and cardiac remodeling. We suggest that decreasing iron-mediated oxidative stress and inflammation offers new therapeutic approaches for obesityinduced cardiomyopathy.Disruption of leptin signaling leads to obesity-induced cardiac remodeling 1,2 , and this progression of cardiac hypertrophy to heart failure is a major contributor to morbidity and mortality in obese patients 3 . Although the pathophysiology of cardiac remodeling in obesity is complex, leptin-deficient (ob/ob) and leptin-resistant (db/ db) signaling serve an important role in obesity-associated left ventricular hypertrophy (LVH) 1,2,4 . The cardiomyopathy that stems from disruption of leptin signaling is due to several factors including insulin resistance, myocardial steatosis, inflammation, oxidative stress, and direct effects of deficiencies in leptin or leptin receptors 1,5,6 . However, the precise role of leptin on obesity-induced cardiomyopathy is not completely understood.Effect of CR on cardiac iron uptake in ob/ob and db/db mice. Due to our observation of elevated cardiac ferrous iron levels in ob/ob mice (Fig. 2f), we examined regulation of iron uptake-related genes via qRT-PCR. LCN2, DMT1, Tfrc, and L-ferritin mRNA levels were significantly lower in ob/ob+CR mice relative to ob/ob and db/db mice fed ad libitum (Figs. S6 and S8). Although the level of 24p3R mRNA in the hearts of ob/ob mice was significantly reduced by CR, we did not observe the same pattern in db/db mice (Figs. S6b and S8b). In addition, CR did not cause the change of iron uptake-related genes in WT and db/m mice ( Figs. S...

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Section: Discussionmentioning

confidence: 99%

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

Lee

Choi

et al. 2020

Sci Rep

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“…The upregulation of TGF-β1 has been observed in lung, liver and kidney fibrosis [12,16,19]. TGF-β1 has been also identified as a key regulator of cardiac fibrosis [25], which may affect cell growth, apoptosis and differentiation, increase ECM production, maintain fibroblast viability, inhibit metalloproteinase production, and facilitate collagen degradation [26]. TGF-β1 activates Smad-dependent and -independent pathways to exhibit its biological activities [27].…”

Section: Tgf-β1mentioning

confidence: 99%

“…Chronic heart failure (CHF) is characterized by the inability of the heart to maintain a normal cardiac output without invoking maladaptive compensatory mechanisms [63]. Several studies have been explored both Smad-dependent and Smad-independent pathways contributed to cardiac fibrosis in TGF-β-induced signaling pathway [25]. In addition to being involved in canonical Smad signaling, TGF-β was also implicated in Smad-independent pathways, which also involve some members of the MAPK family.…”

Section: Tgf-β/smad Signaling Pathway In Cardiac Fibrosismentioning

confidence: 99%

“…Then, transcription factors that were the main targets for activated MAPK stimulated, and this caused the initiation of many downstream signalings. In fact, these downstream signaling pathways play crucial roles in the development of myocardial fibrosis [25]. Taken together, significant activation of TGF-β1/Smad3 and p38MAPK pathways in cardiac fibrosis can lead to myofibroblast proliferation and a marked upregulation of collagen I expression [25].…”

Section: Tgf-β/smad Signaling Pathway In Cardiac Fibrosismentioning

confidence: 99%

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New insights into TGF-β/Smad signaling in tissue fibrosis

Chen

Wang

et al. 2018

Chemico-Biological Interactions

794

480

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Transforming growth factor-β1 (TGF-β1) is considered as a crucial mediator in tissue fibrosis and causes tissue scarring largely by activating its downstream small mother against decapentaplegic (Smad) signaling. Different TGF-β signalings play different roles in fibrogenesis. TGF-β1 directly activates Smad signaling which triggers pro-fibrotic gene overexpression. Excessive studies have demonstrated that dysregulation of TGF-β1/Smad pathway was an important pathogenic mechanism in tissue fibrosis. Smad2 and Smad3 are the two major downstream regulator that promote TGF-β1-mediated tissue fibrosis, while Smad7 serves as a negative feedback regulator of TGF-β1/Smad pathway thereby protects against TGF-β1-mediated fibrosis. This review presents an overview of the molecular mechanisms of TGF-β/Smad signaling pathway in renal, hepatic, pulmonary and cardiac fibrosis, followed by an in-depth discussion of their molecular mechanisms of intervention effects both in vitro and in vivo. The role of TGF-β/Smad signaling pathway in tumor or cancer is also discussed. Additionally, the current advances also highlight targeting TGF-β/Smad signaling pathway for the prevention of tissue fibrosis. The review reveals comprehensive pathophysiological mechanisms of tissue fibrosis. Particular challenges are presented and placed within the context of future applications against tissue fibrosis.

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“…If this modification was blocked, the following steps of TGF-β signaling through the phosphorylation of regulatory Smad2 and Smad3 (R-Smads) would also be terminated [27]. At present, TGF-β was verified as one of the molecular mediators involved in the progression of fibrosis in DCM [28].…”

Section: Introductionmentioning

confidence: 99%

An Inhibition Effect on Diabetic Cardiomyopathy Fibrosis of db/db Mice through Reduction of Myocardial Protein N-glycosylation by Crude 1-DNJ Extract from Homemade <em>Bombyx Batryticatus</em> mori.L

Zhao¹,

Tz²,

Qc³

et al. 2018

Preprint

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The Chinese drug Bombyx Batryticatus mori.L which also named as the white stiff silkworm is widely used in clinics, due to the significant antispasmodic and promotional blood circulation effects. In addition, its hypoglycemic effect is also recognized in recent years. From a pathological point of view, the enzymatic glycosylation and non-enzymatic glycation both have important roles in regulating properties of proteins and are associated with Diabetes. With the db/db mouse model, we examined the alterations of N-glycosylation of diabetic myocardium at primary stage and clarify the differences in glycosylation of myocardium before and after with 1-DNJ treatment. Hydrophilic chromatography solid phase extraction enrichment and LC-MS/MS identification was applied to profile the alternations in protein glycosylation. Meanwhile, N-glycan α1, 6-fucosylation alterations were profiled with LCA lectin blot and FITC-labelled lectin affinity histochemistry. Our results showed that AGES, hydroxyproline, CTGF and other serum indicators and fibrosis related cytokines expressional levels were reduced significantly by 1-DNJ in a dose-dependent manner. In order to verify this result, the well-known pathway of TGF-β/smad2/3 was picked out and α1, 6-core fucosylated TGFR-β Ⅱ was semi-quantified with western blot method. The result sustained the conclusion from LCA lectin affinity histochemistry and lectin blot analysis. The expressional level of α1, 6-fucosyltransferase mRNA was increased in the myocardium of db/db mice, however, the 1-DNJ administration did not show obvious inhibitory effect on FU8expression. This unexpected result can be interpreted as 1-DNJ plays the roles by reducing the concentration of substrate rather than inhibiting α1 ， 6-fucose glycosyltransferase expression. Meanwhile, 1-DNJ crude extract from BBm with some flavonoids accompany can also play the roles of anti-oxidant, and all the chemicals protect the diabetic myocardium from hyperglycemia damage commonly.

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Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy

Cited by 183 publications

References 57 publications

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice

New insights into TGF-β/Smad signaling in tissue fibrosis

An Inhibition Effect on Diabetic Cardiomyopathy Fibrosis of db/db Mice through Reduction of Myocardial Protein N-glycosylation by Crude 1-DNJ Extract from Homemade <em>Bombyx Batryticatus</em> mori.L

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