Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes notably increases the risk for endothelial dysfunction, a main precursor for microvascular complications. While endoplasmic reticulum stress (ERS) and protein tyrosine phosphatase 1B (PTP1B) have been associated with endothelial dysfunction in resistance vessels, whether these mechanisms also contribute to diabetes-mediated endothelial dysfunction in conduit arteries remains unknown. Herein, we tested the hypothesis that diabetes induces macrovascular endothelial dysfunction via endothelial ERS-induced, PTP1B-mediated apoptosis. We showed that diabetes concomitantly increased the expression of PTP1B and of markers of ERS, including GRP78, XBP1, splXBP1 and CHOP in human vessels. Exposure of aortic rings from wild-type mice to the ERS inducers tunicamycin and thapsigargin markedly reduced endothelium-dependent relaxation. Global and endothelial-specific deletion of PTP1B as well as pharmacological inhibition protected aortic rings from ERS-mediated endothelial dysfunction. Nitric oxide synthase inhibition with l-NAME abolished relaxation in the presence and absence of ERS, but neither reactive oxygen species scavenging with tempol or peg-catalase, nor cyclooxygenase inhibition with indomethacin prevented ERS-mediated endothelial dysfunction. However, both p38-MAPK and JNK inhibition protected aortic rings from ERS-mediated endothelial dysfunction. In HUVECs, PTP1B deletion prevented ERS-induced PARP cleavage and apoptosis. Lastly, acute ERS inhibition in aortic rings and selective deficiency of endothelial PTP1B in mice protected mice from diabetes-induced endothelial dysfunction. Altogether, these data support the contribution of the p38/JNK-apoptosis pathway in ERS-mediated endothelial dysfunction and present endothelial PTP1B as a major regulator of endothelial cell viability in conduit vessels and a potential target for the management of macrovascular diseases in diabetes.
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PMID:Selective deficiency in endothelial PTP1B protects from diabetes and endoplasmic reticulum stress-associated endothelial dysfunction via preventing endothelial cell apoptosis. 3241 88

Disruption of extravillous trophoblast (EVT) migration and invasion is considered to be responsible for pathological placentation in preeclampsia (PE). Cyclin G2 (CCNG2) is an atypical cyclin that inhibits cell cycle progression. However, its biological function and underlying molecular mechanism in PE are poorly understood. In this study, clinical data demonstrated that CCNG2 was significantly upregulated in PE placenta and associated with invasive EVT dysfunction. Additionally, Ccng2 knockout led to an attenuation of PE-like symptoms in the PE mouse model produced via treatment with NG-nitro-L-arginine methyl ester (L-NAME). In vitro, CCNG2 inhibited the migration, invasion, and endothelial-like network formation of human trophoblast cell line HTR8/SVneo. Mechanically, CCNG2 suppressed JNK-dependent Wnt/PCP signaling and its downstream indicators including epithelial-to-mesenchymal transition (EMT) markers and matrix metalloproteinases (MMPs) via promoting the polyubiquitination degradation of dishevelled 2 (Dvl2) protein in HTR8/SVneo cells. We also discovered that the E3 ligase Ring finger protein 123 (RNF123), as a novel CCNG2 target among HTR8/SVneo cells, interacted with Dvl2 and participated in CCNG2-induced polyubiquitination degradation of Dvl2. Moreover, we verified that the treatment of HTR8/SVneo cells with RNF123-specific siRNA improved polyubiquitination-induced degradation of Dvl2 and the activity of Wnt/PCP-JNK signaling mediated by CCNG2. Taken together, our results reveal that the CCNG2/RNF123/Dvl2/JNK axis may be involved in the pathogenesis and progression of PE through trophoblastic cell function modulation, thus probably providing us with new therapeutic strategies for PE treatment.
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PMID:Cyclin G2 upregulation impairs migration, invasion, and network formation through RNF123/Dvl2/JNK signaling in the trophoblast cell line HTR8/SVneo, a possible role in preeclampsia. 3320 77


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