Differential regulation of collagen types I and III expression in cardiac fibroblasts by AGEs through TRB3/MAPK signaling pathway

Tang, Mengxiong; Zhong, Ming; Shang, Yuan-yuan; Lin, Haiyan; Deng, Jingjing; Jiang, Hong; Lu, Huixia; Zhang, Y.; Zhang, W.

doi:10.1007/s00018-008-8255-3

Cited by 60 publications

(45 citation statements)

References 31 publications

(42 reference statements)

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“…The activation of NF-κB, which is downstream of mitogen-activated protein kinases, has also been shown to participate in several physiological processes in cardiac fibroblasts [27] . The activation of ERK1/2 and NF-κB has been shown to be involved in collagen deposition in the hearts of diabetic and hypertensive animals [28][29][30][31] . Ang II and glucose-induced collagen accumulation in the cultured cardiac fibroblasts has also been demonstrated to involve the activation of ERK1/2 and NF-κB [10,12,32] .…”

Section: Discussionmentioning

confidence: 99%

Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

et al. 2016

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Aim: Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors can not only lower blood glucose levels, but also alleviate cardiac remodeling after myocardial ischemia and hypertension. In the present study, we investigated the effects of a DPP-4 inhibitor (linagliptin) and a GLP-1 activator (liraglutide) on glucose-and angiotensin II (Ang II)-induced collagen formation and cytoskeleton reorganization in cardiac fibroblasts in vitro, and elucidated the related mechanisms. Methods: Cardiac fibroblasts were isolated from the hearts of 6-week-old C57BL/6 mice, and then exposed to different concentrations of glucose or Ang II for 24 h. The expression of fibrotic signals (fibronectin, collagen-1, -3 and -4), as well as ERK1/2 and NF-κB-p65 in the fibroblasts was examined using Western blotting assays. F-actin degradation was detected under inverted laser confocal microscope in fibroblasts stained with Rhodamine phalloidin. Results: Glucose (1-40 mmol/L) and Ang II (10-5 mol/L) dose-dependently increased the expression of fibronectin, collagens, phospho-ERK1/2 and phospho-NF-κB-p65 in cardiac fibroblasts. High concentrations of glucose (≥40 mmol/L) and Ang II (≥10 -6 mol/L) caused a significant degradation of F-actin (less assembly F-actin fibers and more disassembly fibers). ERK1/2 inhibitor U0126 (10 μmol/L) and NF-κB inhibitor JSH-23 (10 μmol/L) both markedly suppressed glucose-and angiotensin II-induced fibronectin and collagen expressions in cardiac fibroblasts. Furthermore, pretreatment with liraglutide (10-100 nmol/L) or linagliptin (3 and 30 nmol/L) significantly decreased glucose-and Ang II-induced expression of fibrotic signals, phospho-ERK1/2 and phospho-NF-κB-p65 in cardiac fibroblasts. Moreover, pretreatment with liraglutide (30 nmol/L) or liraglutide (100 nmol/L) markedly inhibited glucose-induced F-actin degradation, however, only liraglutide inhibited Ang II-induced F-actin degradation. Conclusion: Linagliptin and liraglutide inhibit glucose-and Ang II-induced collagen formation in cardiac fibroblasts via activation of the ERK/NF-κB/pathway. Linagliptin and liraglutide also markedly inhibit glucose-induced F-actin degradation in cardiac fibroblasts, but only liraglutide inhibits Ang II-induced F-actin degradation.

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Section: Discussionmentioning

confidence: 99%

Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

et al. 2016

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“…In diabetic cardiomyopathy, advanced glycation end products cause collagen deposition through activation of ERK1/2 and p38-MAPK. After inhibiting TRIB3 with small-interfering RNA, phosphorylation of both ERK1/2 and p38-MAPK by advanced glycation end products was attenuated (54). TRIB3 proteins appear to act as activators and inhibitors of MAPK activity, depending on the ratio of TRIB3 to MAPKK in the cell.…”

Section: E571 Trib3 Impairs Insulin Action In Skeletal Musclementioning

confidence: 98%

MammalianTribbleshomolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

Liu

Franklin

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Tribbles homolog 3 (TRIB3) was found to inhibit insulin-stimulated Akt phosphorylation and modulate gluconeogenesis in rodent liver. Currently, we examined a role for TRIB3 in skeletal muscle insulin resistance. Ten insulin-sensitive, ten insulin-resistant, and ten untreated type 2 diabetic (T2DM) patients were metabolically characterized by hyperinsulinemic euglycemic glucose clamps, and biopsies of vastus lateralis were obtained. Skeletal muscle samples were also collected from rodent models including streptozotocin (STZ)-induced diabetic rats, db/db mice, and Zucker fatty rats. Finally, L6 muscle cells were used to examine regulation of TRIB3 by glucose, and stable cell lines hyperexpressing TRIB3 were generated to identify mechanisms underlying TRIB3-induced insulin resistance. We found that 1) skeletal muscle TRIB3 protein levels are significantly elevated in T2DM patients; 2) muscle TRIB3 protein content is inversely correlated with glucose disposal rates and positively correlated with fasting glucose; 3) skeletal muscle TRIB3 protein levels are increased in STZ-diabetic rats, db/db mice, and Zucker fatty rats; 4) stable TRIB3 hyperexpression in muscle cells blocks insulin-stimulated glucose transport and glucose transporter 4 (GLUT4) translocation and impairs phosphorylation of Akt, ERK, and insulin receptor substrate-1 in insulin signal transduction; and 5) TRIB3 mRNA and protein levels are increased by high glucose concentrations, as well as by glucose deprivation in muscle cells. These data identify TRIB3 induction as a novel molecular mechanism in human insulin resistance and diabetes. TRIB3 acts as a nutrient sensor and could mediate the component of insulin resistance attributable to hyperglycemia (i.e., glucose toxicity) in diabetes. glucose toxicity; type 2 diabetes; insulin signaling THE PREVALENCE OF TYPE 2 DIABETES MELLITUS (T2DM) is rapidly increasing in Westernized nations. Although it likely results from both genetic and environment factors, a key pathogenic characteristic of T2DM is insulin resistance, due to impaired stimulation of glucose uptake in skeletal muscle.To obtain a more comprehensive understanding of insulin resistance, we have performed cDNA microarray studies to systematically assess differential gene expression in skeletal muscle from insulin-sensitive (IS) vs. insulin-resistant (IR) humans (59, 60). These analyses identified Tribbles homolog 3 (TRIB3) as a gene with increased expression in patients with T2DM. Tribbles was first identified by Mata et al. (31) in 2000 as a regulator of germ-cell development in Drosophila (31). Tribbles inhibits mitosis and regulates DNA damage repair by promoting ubiquitination and proteasome-mediated degradation of specific cell cycle regulators early in development (17,31,46,49). Mammals express a family of three genes, TRIB1, TRIB2, and TRIB3, that are homologous to Tribbles. These family members are characterized by a variant kinase domain in the center of molecule with a high homology to serine/ threonine kinases (22). However, they app...

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“…The interacting partners of TRB3 range from transcription factors, ubiquitin ligase, BMP type II receptor to members of the MAPK and PI3K signaling pathways. Through interacting with these proteins, it coordinates crucial cellular processes, including glucose and lipid metabolism, apoptosis, adipocyte differentiation, cell stress and regulation of collagen expression (Bezy et al, 2007;Chan et al, 2007;Du et al, 2003;Ohoka et al, 2005;Qi et al, 2006;Tang et al, 2008). Recently, emerging evidence suggests that the three mammalian tribbles homologs are crucial modulators of tumorogenesis.…”

Section: Introductionmentioning

confidence: 99%

TRB3 interacts with SMAD3 promoting tumor cell migration and invasion

Hua

Liu

et al. 2011

Journal of Cell Science

122

119

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SummaryTribbles homolog 3 (TRB3, also known as TRIB3, NIPK and SKIP3), a human homolog of Drosophila Tribbles, has been found to interact with a variety of signaling molecules to regulate diverse cellular functions. Here, we report that TRB3 is a novel SMAD3-interacting protein. Expression of exogenous TRB3 enhanced the transcriptional activity of SMAD3, whereas knocking down endogenous TRB3 reduced the transcriptional activity of SMAD3. The kinase-like domain (KD) of TRB3 was responsible for the interaction with SMAD3 and the regulation of SMAD3-mediated transcriptional activity. In addition, TGF-b1 stimulation or overexpression of SMAD3 enhanced the TRB3 promoter activity and expression, suggesting that there is a positive feedback loop between TRB3 and TGF-b-SMAD3 signaling. Mechanistically, TRB3 was found to trigger the degradation of SMAD ubiquitin regulatory factor 2 (Smurf2), which resulted in a decrease in the degradation of SMAD2 and phosphorylated SMAD3. Moreover, TRB3-SMAD3 interaction promoted the nuclear localization of SMAD3 because of the interaction of TRB3 with the MH2 domain of SMAD3. These effects of TRB3 were responsible for potentiating the SMAD3-mediated activity. Furthermore, knockdown of endogenous TRB3 expression inhibited the migration and invasion of tumor cells in vitro, which were associated with an increase in the expression of Ecadherin and a decrease in the expression of Twist-1 and Snail, two master regulators of epithelial-to-mesenchymal transition, suggesting a crucial role for TRB3 in maintaining the mesenchymal status of tumor cells. These results demonstrate that TRB3 acts as a novel SMAD3-interacting protein to participate in the positive regulation of TGF-b-SMAD-mediated cellular biological functions.

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Differential regulation of collagen types I and III expression in cardiac fibroblasts by AGEs through TRB3/MAPK signaling pathway

Cited by 60 publications

References 31 publications

Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

MammalianTribbleshomolog 3 impairs insulin action in skeletal muscle: role in glucose-induced insulin resistance

TRB3 interacts with SMAD3 promoting tumor cell migration and invasion

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