Dihazi, Hassan

[["dc.bibliographiccitation.artnumber","1325"],["dc.bibliographiccitation.journal","Frontiers in Physiology"],["dc.bibliographiccitation.volume","9"],["dc.contributor.author","Lipphardt, Mark"],["dc.contributor.author","Dihazi, Hassan"],["dc.contributor.author","Müller, Gerhard A."],["dc.contributor.author","Goligorsky, Michael S."],["dc.date.accessioned","2019-07-09T11:45:55Z"],["dc.date.available","2019-07-09T11:45:55Z"],["dc.date.issued","2018"],["dc.description.abstract","Sirtuins (SIRT) are ubiquitous histone and protein deacetylases and a member of this family, SIRT1, is the best-studied one. Its functions in endothelial cells encompass branching angiogenesis, activation of endothelial nitric oxide synthase, regulation of proapoptotic and proinflammatory pathways, among others. Defective SIRT1 activity has been described in various cardiovascular, renal diseases and in aging-associated conditions. Therefore, understanding of SIRT1-deficient, endothelial dysfunctional phenotype has much to offer clinically. Here, we summarize recent studies by several investigative teams of the characteristics of models of global endothelial SIRT1 deficiency, the causes of facilitative development of fibrosis in these conditions, dissect the protein composition of the aberrant secretome of SIRT1-deficient endothelial cells and present several components of this aberrant secretome that are involved in fibrogenesis via activation of fibroblasts to myofibroblasts. These include ligands of Wnt and Notch pathways, as well as proteolytic fragments of glycocalyx core protein, syndecan-4. The latter finding is crucial for understanding the degradation of glycocalyx that accompanies SIRT1 deficiency. This spectrum of abnormalities associated with SIRT1 deficiency in endothelial cells is essential for understanding the origins and features of endothelial dysfunction in a host of cardiovascular and renal diseases."],["dc.identifier.doi","10.3389/fphys.2018.01325"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15344"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59337"],["dc.language.iso","en"],["dc.notes.intern","DeepGreen Import"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1664-042X"],["dc.relation.issn","1664-042X"],["dc.rights","http://creativecommons.org/licenses/by/4.0/"],["dc.subject.ddc","610"],["dc.title","Fibrogenic Secretome of Sirtuin 1-Deficient Endothelial Cells: Wnt, Notch and Glycocalyx Rheostat"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","H484"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","American Journal of Physiology. Heart and Circulatory Physiology"],["dc.bibliographiccitation.lastpage","H496"],["dc.bibliographiccitation.volume","314"],["dc.contributor.author","Lipphardt, Mark"],["dc.contributor.author","Song, Jong W"],["dc.contributor.author","Ratliff, Brian B"],["dc.contributor.author","Dihazi, Hassan"],["dc.contributor.author","Müller, Gerhard A"],["dc.contributor.author","Goligorsky, Michael S"],["dc.date.accessioned","2019-07-09T11:45:25Z"],["dc.date.available","2019-07-09T11:45:25Z"],["dc.date.issued","2018"],["dc.description.abstract","Syndecan-4 (Synd4) is a member of the membrane-spanning, glycocalyx-forming proteoglycan family. It has been suggested that Synd4 participates in renal fibrosis. We compared wild-type and fibrosis-prone endothelial sirtuin 1-deficient (Sirt1endo-/-) mice, the latter being a model of global endothelial dysfunction. We performed mass spectrometry analysis, which revealed that Synd4 was highly enriched in the secretome of renal microvascular endothelial cells obtained from Sirt1endo-/- mice upon stimulation with transforming growth factor-β1; notably, all detectable peptides were confined to the ectodomain of Synd4. Elevated Synd4 was due to enhanced NF-κB signaling in Sirt1endo-/- mice, while its shedding occurred as a result of oxidative stress in Sirt1 deficiency. Synd4 expression was significantly enhanced after unilateral ureteral obstruction compared with contralateral kidneys. Furthermore, hyperplasia of renal myofibroblasts accompanied by microvascular rarefaction and overexpression of Synd4 were detected in Sirt1endo-/- mice. The ectodomain of Synd4 acted as a chemoattractant for monocytes with higher levels of macrophages and higher expression levels of Synd4 in the extracellular matrix of Sirt1endo-/- mice. In vitro, ectodomain application resulted in generation of myofibroblasts from cultured renal fibroblasts, while in vivo, subcapsular injection of ectodomain increased interstitial fibrosis. Moreover, the endothelial glycocalyx was reduced in Sirt1endo-/- mice, highlighting the induction of Synd4 occurring in parallel with the depletion of its intact form and accumulation of its ectodomain in Sirt1endo-/- mice. On the basis of our experimental results, we propose that it is the Synd4 ectodomain per se that is partially responsible for fibrosis in unilateral ureteral obstruction, especially when it is combined with endothelial dysfunction. NEW & NOTEWORTHY Our findings suggest that endothelial dysfunction induces the expression of syndecan-4 via activation of the NF-κB pathway. Furthermore, we show that syndecan-4 is shed to a greater amount because of increased oxidative stress in dysfunctional endothelial cells and that the release of the syndecan-4 ectodomain leads to tubulointerstitial fibrosis."],["dc.identifier.doi","10.1152/ajpheart.00548.2017"],["dc.identifier.pmid","29101181"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15199"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59225"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1522-1539"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.title","Endothelial dysfunction is a superinducer of syndecan-4: fibrogenic role of its ectodomain."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]