WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA540306 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Bulk RNA-seq heart left ventricle data from wild type and WWP2 gene mutant mice (after 28 days of angiotensinII treatment)
2019-07-08 | GSE130468 | GEO
Project description:Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.
| S-EPMC6689010 | biostudies-literature
Project description:Overall goal: To elucidate fibroblast-specific role of TGFβ-Smad2/3 signaling in fibroblast activation and their differentiation to myofibroblasts. Purpose of analysis: To generate transcriptional profile of Smad2/3 and TGFβreceptors1/2-deficient fibroblasts in the context of pathological cardiac fibrosis.
2017-10-25 | GSE101772 | GEO
Project description:Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac remodelling. Recent evidence implicates monocytes/macrophages modulating cardiac fibrosis but targeting these is convoluted, giving their tissue heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis. Here we focus on the role of WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that its myeloid-specific deletion reduces cardiac fibrosis in hypertension-induced NICM. Using the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase driven by Ccl5-expressing Ly6chigh monocytes. Among other cardiac macrophage subtypes, WWP2 dysfunction primarily affects the Ccl5-dependent infiltration and activation of Ly6chigh monocytes, which causes reduced myofibroblast trans-differentiation. WWP2 interacts with IRF7, promoting its non-degradative monoubiquitination, nuclear translocation and transcriptional activity, including upstream Ccl5. Thus, we identify WWP2 as a key regulator of IRF7-mediated Ccl5/Ly6chigh monocyte axis in heart fibrosis.
2022-10-25 | GSE198003 | GEO
Project description:Renal fibrosis is a common pathological endpoint that is challenging to reverse in chronic kidney disease (CKD) independently of the underlying causes. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM), recent reports revealed their heterogeneity in proliferative and fibrotic activities, mirroring specific metabolic states that drive fibrosis. Here, we investigate the role of E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of renal myofibroblasts in fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients and in pre-clinical models of CKD. WWP2 deficiency leads to increased fatty acid oxidation, boosting mitochondrial respiration, promoting myofibroblast proliferation and arresting pro-fibrotic activation, thus ameliorating kidney fibrosis. Specifically, WWP2 suppresses the transcription of PGC-1α, which mediates the metabolic and proliferative changes in fibrotic myofibroblasts. Pharmacological intervention targeting PGC-1α reverses the pro-fibrotic effect of WWP2. These findings reveal a previously unappreciated WWP2-PGC-1α axis underlying the metabolic reprogramming of myofibroblasts during renal fibrosis, which could provide a new target for therapeutic intervention in CKD.
2024-05-19 | GSE267765 | GEO
Project description:Renal fibrosis is a common pathological endpoint that is challenging to reverse in chronic kidney disease (CKD) independently of the underlying causes. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM), recent reports revealed their heterogeneity in proliferative and fibrotic activities, mirroring specific metabolic states that drive fibrosis. Here, we investigate the role of E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of renal myofibroblasts in fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients and in pre-clinical models of CKD. WWP2 deficiency leads to increased fatty acid oxidation, boosting mitochondrial respiration, promoting myofibroblast proliferation and arresting pro-fibrotic activation, thus ameliorating kidney fibrosis. Specifically, WWP2 suppresses the transcription of PGC-1α, which mediates the metabolic and proliferative changes in fibrotic myofibroblasts. Pharmacological intervention targeting PGC-1α reverses the pro-fibrotic effect of WWP2. These findings reveal a previously unappreciated WWP2-PGC-1α axis underlying the metabolic reprogramming of myofibroblasts during renal fibrosis, which could provide a new target for therapeutic intervention in CKD.
2024-02-05 | GSE241502 | GEO
Project description:Renal fibrosis is a common pathological endpoint that is challenging to reverse in chronic kidney disease (CKD) independently of the underlying causes. Although myofibroblasts are mainly responsible for the accumulation of a fibrillar collagen-rich extracellular matrix (ECM), recent reports revealed their heterogeneity in proliferative and fibrotic activities, mirroring specific metabolic states that drive fibrosis. Here, we investigate the role of E3 ubiquitin-protein ligase WWP2 in the metabolic reprogramming of renal myofibroblasts in fibrosis. The tubulointerstitial expression of WWP2 contributes to the progression of fibrosis in CKD patients and in pre-clinical models of CKD. WWP2 deficiency leads to increased fatty acid oxidation, boosting mitochondrial respiration, promoting myofibroblast proliferation and arresting pro-fibrotic activation, thus ameliorating kidney fibrosis. Specifically, WWP2 suppresses the transcription of PGC-1α, which mediates the metabolic and proliferative changes in fibrotic myofibroblasts. Pharmacological intervention targeting PGC-1α reverses the pro-fibrotic effect of WWP2. These findings reveal a previously unappreciated WWP2-PGC-1α axis underlying the metabolic reprogramming of myofibroblasts during renal fibrosis, which could provide a new target for therapeutic intervention in CKD.
2024-02-05 | GSE241503 | GEO
Project description:Smad2 and Smad3 (Smad2/3) primarily mediates the transforming growth factor-β (TGF-β) signaling that drives cell proliferation, differentiation, and migration. The dynamics of the Smad2/3 phosphorylation provides the key mechanism for regulating the TGF-β signaling pathway. Here we identified NLK as a novel regulator of TGF-β signaling pathway via modulating the phosphorylation of Smad2/3 in the linker region.
2021-09-10 | PXD023957 | Pride
Project description:CDC-like Kinase 4 Deficiency Contributes to Pathological Cardiac Hypertrophy by Modulating NEXN Phosphorylation
| PRJNA782453 | ENA
Project description:WWP2 regulates Ly6Chigh monocyte infiltration and activity in heart fibrosis
| PRJNA813315 | ENA