Simvastatin reduces TGF-β1-induced SMAD2/3-dependent human ventricular fibroblasts differentiation: Role of protein phosphatase activation

Abstract Introduction The progression of paroxysmal AF (PAF) to persistent AF (PsAF) worsens the prognosis of AF, but its underlying mechanisms remain elusive. Recently, circular RNAs (circRNAs) were reported to be associated with cardiac fibrosis. In case of the vital role of cardiac fibrosis in AF persistency, we hypothesis that circRNAs may be potential regulators in the process of AF progression. Materials and methods 6 persistent and 6 paroxysmal AF patients were enrolled as derivation cohort. Plasma circRNAs expressions were determined by microarray and validated by RT-PCR. Fibrosis level, manifested by serum TGF-β, was determined by ELISA. Pathways and related non-coding RNAs involving in the progression of AF regulated were predicted by in silico analysis. Results PsAF patients showed a distinct circRNAs expression profile with 92 circRNAs significantly dysregulated (fold change ≥ 2, p < 0.05), compared with PAF patients. The validity of the expression patterns was subsequently validated by RT-PCR in another 60 AF patients (30 PsAF and PAF, respectively). In addition, all the 5 up and down regulated circRNAs were clustered in MAPK and TGF-beta signaling pathway by KEGG pathway analysis. Among the 5 circRNAs, hsa_circ_0004104 was consistently downregulated in PsAF group (0.6 ± 0.33 vs 1.46 ± 0.41, p < 0.001) and predicted to target several AF and/or cardiac fibrosis related miRNAs reported by previous studies. In addition, TGF-β1 level was significantly higher in the PsAF group (5560.23 ± 1833.64 vs 2236.66 ± 914.89, p < 0.001), and hsa_circ_0004104 showed a significant negative correlation with TGF-β1 level (r = − 0.797, p < 0.001). Conclusion CircRNAs dysregulation plays vital roles in AF persistency. hsa_circ_0004104 could be a potential regulator and biomarker in AF persistency by promoting cardiac fibrosis via targeting MAPK and TGF-beta pathways.

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Krill oil and low-dose aspirin combination mitigates experimentally induced silicosis in rats: role of NF-κB/TGF-β1/MMP-9 pathway

Environmental Science and Pollution Research ◽

10.1007/s11356-020-11921-7 ◽

2021 ◽

Author(s):

Ahmed G. Abd Elhameed

Keyword(s):

Low Dose ◽

Krill Oil ◽

Dose Aspirin ◽

Low Dose Aspirin ◽

Tgf Β1 ◽

Experimentally Induced

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Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis

Scientific Reports ◽

10.1038/s41598-020-78056-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jonghwa Kim ◽

Wonseok Kang ◽

So Hee Kang ◽

Su Hyun Park ◽

Ji Young Kim ◽

...

Keyword(s):

Liver Fibrosis ◽

Tyrosine Kinase ◽

Focal Adhesion ◽

Transforming Growth Factor ◽

Family Members ◽

Type I ◽

Tyrosine Kinase 2 ◽

The Impact ◽

Tgf Β1

AbstractHepatic fibrogenesis is characterized by activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix (ECM). The impact of ECM on TGF-β-mediated fibrogenic signaling pathway in HSCs has remained obscure. We studied the role of non-receptor tyrosine kinase focal adhesion kinase (FAK) family members in TGF-β-signaling in HSCs. We used a CCl4-induced liver fibrosis mice model to evaluate the effect of FAK family kinase inhibitors on liver fibrosis. RT-PCR and Western blot were used to measure the expression of its target genes; α-SMA, collagen, Nox4, TGF-β1, Smad7, and CTGF. Pharmacological inhibitors, siRNA-mediated knock-down, and plasmid-based overexpression were adopted to modulate the function and the expression level of proteins. Association of PYK2 activation with liver fibrosis was confirmed in liver samples from CCl4-treated mice and patients with significant fibrosis or cirrhosis. TGF-β treatment up-regulated expression of α-SMA, type I collagen, NOX4, CTGF, TGF-β1, and Smad7 in LX-2 cells. Inhibition of FAK family members suppressed TGF-β-mediated fibrogenic signaling. SiRNA experiments demonstrated that TGF-β1 and Smad7 were upregulated via Smad-dependent pathway through FAK activation. In addition, CTGF induction was Smad-independent and PYK2-dependent. Furthermore, RhoA activation was essential for TGF-β-mediated CTGF induction, evidenced by using ROCK inhibitor and dominant negative RhoA expression. We identified that TGF-β1-induced activation of PYK2-Src-RhoA triad leads to YAP/TAZ activation for CTGF induction in liver fibrosis. These findings provide new insights into the role of focal adhesion molecules in liver fibrogenesis, and targeting PYK2 may be an attractive target for developing novel therapeutic strategies for the treatment of liver fibrosis.

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Novel role of the protein phosphatase 1 regulatory subunit PPP1R3A in atrial fibrillation

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2018.07.077 ◽

2018 ◽

Vol 124 ◽

pp. 108

Author(s):

Katherina Alsina ◽

Mohit Hulsurkar ◽

Chunxia Yao ◽

Barbara Langer ◽

David Chiang ◽

...

Keyword(s):

Atrial Fibrillation ◽

Protein Phosphatase ◽

Protein Phosphatase 1 ◽

Regulatory Subunit

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Ref2, a regulatory subunit of the yeast protein phosphatase 1, is a novel component of cation homoeostasis

Biochemical Journal ◽

10.1042/bj20091909 ◽

2010 ◽

Vol 426 (3) ◽

pp. 355-364 ◽

Cited By ~ 12

Author(s):

Jofre Ferrer-Dalmau ◽

Asier González ◽

Maria Platara ◽

Clara Navarrete ◽

José L. Martínez ◽

...

Keyword(s):

Protein Phosphatase ◽

Living Organism ◽

Calcium Sensitivity ◽

Growth Conditions ◽

Protein Phosphatase 1 ◽

Regulatory Subunit ◽

Alkaline Ph ◽

Yeast Protein ◽

Increased Sensitivity

Maintenance of cation homoeostasis is a key process for any living organism. Specific mutations in Glc7, the essential catalytic subunit of yeast protein phosphatase 1, result in salt and alkaline pH sensitivity, suggesting a role for this protein in cation homoeostasis. We screened a collection of Glc7 regulatory subunit mutants for altered tolerance to diverse cations (sodium, lithium and calcium) and alkaline pH. Among 18 candidates, only deletion of REF2 (RNA end formation 2) yielded increased sensitivity to these conditions, as well as to diverse organic toxic cations. The Ref2F374A mutation, which renders it unable to bind Glc7, did not rescue the salt-related phenotypes of the ref2 strain, suggesting that Ref2 function in cation homoeostasis is mediated by Glc7. The ref2 deletion mutant displays a marked decrease in lithium efflux, which can be explained by the inability of these cells to fully induce the Na+-ATPase ENA1 gene. The effect of lack of Ref2 is additive to that of blockage of the calcineurin pathway and might disrupt multiple mechanisms controlling ENA1 expression. ref2 cells display a striking defect in vacuolar morphogenesis, which probably accounts for the increased calcium levels observed under standard growth conditions and the strong calcium sensitivity of this mutant. Remarkably, the evidence collected indicates that the role of Ref2 in cation homoeostasis may be unrelated to its previously identified function in the formation of mRNA via the APT (for associated with Pta1) complex.

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Identification of a microRNA signature in renal fibrosis: role of miR-21

AJP Renal Physiology ◽

10.1152/ajprenal.00273.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. F793-F801 ◽

Cited By ~ 169

Author(s):

Abolfazl Zarjou ◽

Shanzhong Yang ◽

Edward Abraham ◽

Anupam Agarwal ◽

Gang Liu

Keyword(s):

Epithelial Cells ◽

Renal Fibrosis ◽

Transforming Growth Factor ◽

Response To Treatment ◽

Tubular Epithelial Cells ◽

Altered Expression ◽

Tnf Α ◽

Tgf Β1

Renal fibrosis is a final stage of many forms of kidney disease and leads to impairment of kidney function. The molecular pathogenesis of renal fibrosis is currently not well-understood. microRNAs (miRNAs) are important players in initiation and progression of many pathologic processes including diabetes, cancer, and cardiovascular disease. However, the role of miRNAs in kidney injury and repair is not well-characterized. In the present study, we found a unique miRNA signature associated with unilateral ureteral obstruction (UUO)-induced renal fibrosis. We found altered expression in UUO kidneys of miRNAs that have been shown to be responsive to stimulation by transforming growth factor (TGF)-β1 or TNF-α. Among these miRNAs, miR-21 demonstrated the greatest increase in UUO kidneys. The enhanced expression of miR-21 was located mainly in distal tubular epithelial cells. miR-21 expression was upregulated in response to treatment with TGF-β1 or TNF-α in human renal tubular epithelial cells in vitro. Furthermore, we found that blocking miR-21 in vivo attenuated UUO-induced renal fibrosis, presumably through diminishing the expression of profibrotic proteins and reducing infiltration of inflammatory macrophages in UUO kidneys. Our data suggest that targeting specific miRNAs could be a novel therapeutic approach to treat renal fibrosis.

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The Role of Arg13 in Protein Phosphatase M tPphA from Thermosynechococcus elongatus

Enzyme Research ◽

10.1155/2012/272706 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Jiyong Su ◽

Karl Forchhammer

Keyword(s):

Amino Acid ◽

Protein Phosphatase ◽

Arginine Residue ◽

Side Chain ◽

Wild Type ◽

Catalytic Center ◽

Nitrophenyl Phosphate ◽

Reduced Activity ◽

Amino Acid Variants

A highly conserved arginine residue is close to the catalytic center of PPM/PP2C-type protein phosphatases. Different crystal structures of PPM/PP2C homologues revealed that the guanidinium side chain of this arginine residue can adopt variable conformations and may bind ligands, suggesting an important role of this residue during catalysis. In this paper, we randomly mutated Arginine 13 of tPphA, a PPM/PP2C-type phosphatase from Thermosynechococcus elongatus, and obtained 18 different amino acid variants. The generated variants were tested towards p-nitrophenyl phosphate and various phosphopeptides. Towards p-nitrophenyl phosphate as substrate, twelve variants showed 3–7 times higher Km values than wild-type tPphA and four variants (R13D, R13F, R13L, and R13W) completely lost activity. Strikingly, these variants were still able to dephosphorylate phosphopeptides, although with strongly reduced activity. The specific inability of some Arg-13 variants to hydrolyze p-nitrophenyl phosphate highlights the importance of additional substrate interactions apart from the substrate phosphate for catalysis. The properties of the R13 variants indicate that this residue assists in substrate binding.

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