The metalloproteinase ADAM15 is upregulated by shear stress and promotes survival of endothelial cells

Babendreyer, Aaron; Molls, Lisa; Simons, Indra M.; Dreymueller, Daniela; Biller, Kristina; Jahr, Holger; Denecke, Bernd; Boon, Reinier A.; Bette, Sebastian; Schnakenberg, Uwe; Ludwig, Andreas

doi:10.1016/j.yjmcc.2019.06.017

Cited by 22 publications

(14 citation statements)

References 46 publications

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“…The expression of known flow-induced genes KLF2 , KLF4 , and eNOS ( NOS3 ), which regulate vascular tone ( Sangwung et al, 2017 ), were highly upregulated in flow ( Figure 5A and Supplementary Tables S1A–C ). In addition, the expression of anti-atherogenic genes ( CYP1A1 , CYP1B1 , and PLPP3 ) ( Conway et al, 2009 ; Mueller et al, 2019 ), genes that promote vascular homeostasis and EC survival ( SLC9A3R2, PODXL , and ADAM15 ) ( Bhattacharya et al, 2012 ; Horrillo et al, 2016 ; Babendreyer et al, 2019 ) and stress response markers ( HMOX1 and NQO1 ) ( Dinkova-Kostova and Talalay, 2000 ; Issan et al, 2014 ) were upregulated by flow ( Figure 5A and Supplementary Tables S1A–C ). In contrast, shear stress significantly downregulated the vascular tone regulator EDN1 ( Yanagisawa et al, 1988 ) in all flow clusters ( Figure 5B and Supplementary Tables S1A–C ).…”

Section: Resultsmentioning

confidence: 99%

Flow-Induced Transcriptomic Remodeling of Endothelial Cells Derived From Human Induced Pluripotent Stem Cells

et al. 2020

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The vascular system is essential for the development and function of all organs and tissues in our body. The molecular signature and phenotype of endothelial cells (EC) are greatly affected by blood flow-induced shear stress, which is a vital component of vascular development and homeostasis. Recent advances in differentiation of ECs from human induced pluripotent stem cells (hiPSC) have enabled development of in vitro experimental models of the vasculature containing cells from healthy individuals or from patients harboring genetic variants or diseases of interest. Here we have used hiPSCderived ECs and bulk-and single-cell RNA sequencing to study the effect of flow on the transcriptomic landscape of hiPSC-ECs and their heterogeneity. We demonstrate that hiPS-ECs are plastic and they adapt to flow by expressing known flow-induced genes. Single-cell RNA sequencing showed that flow induced a more homogenous and homeostatically more stable EC population compared to static cultures, as genes related to cell polarization, barrier formation and glucose and fatty acid transport were induced. The hiPS-ECs increased both arterial and venous markers when exposed to flow. Interestingly, while in general there was a greater increase in the venous markers, one cluster with more arterial-like hiPS-ECs was detected. Single-cell RNA sequencing revealed that not all hiPS-ECs are similar even after sorting, but exposing them to flow increases their homogeneity. Since hiPS-ECs resemble immature ECs and demonstrate high plasticity in response to flow, they provide an excellent model to study vascular development.

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Section: Resultsmentioning

confidence: 99%

Flow-Induced Transcriptomic Remodeling of Endothelial Cells Derived From Human Induced Pluripotent Stem Cells

et al. 2020

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“…Short hairpin RNA (shRNA) targeting ADAM10 (5 CGC GTC CCC ACA GTG CAG TCC AAG TCA ATT CAA GAG ATT GAC TTG GAC TGC ACT GTT TTT TGG AAA T 3 ) or ADAM17 (5 CGC GTC CCC AGG AAA GCC CTG TAC AGT ATT CAA GAG ATA CTG TAC AGG GCT TTC CTT TTT TGG AAA T 3 ) was inserted into the lentiviral expression vector pLVTHM-CFP and shRNA targeting iRhom2 (GTG AAG CAC TTT GCC TTT GAT CTC GAG ATC AAA GGC AAA GTG CTT CAC TTT TTG) was inserted into the lentiviral expression vector pLKO.1 as described [45,46]. Inserted irrelevant shRNA (pLVTHM-CFP/mCherry; 5 CGC GTC CCC ACC GTC TGT GTA TCG TCG CTT CAA GAG AGC GAC GAT ACA CAG ACG GTT TTT TGG AAA T 3 ) and pLKO.1 non-mammalian shRNA control plasmid DNA (SHC002, Merck, Darmstadt, Germany) served as a control.…”

Section: Cell Culture and Transductionmentioning

confidence: 99%

The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

Seifert

Wozniak

Düsterhöft

et al. 2020

IJMS

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Uptake of bacteria by phagocytes is a crucial step in innate immune defence. Members of the disintegrin and metalloproteinase (ADAM) family critically control the immune response by limited proteolysis of surface expressed mediator molecules. Here, we investigated the significance of ADAM17 and its regulatory adapter molecule iRhom2 for bacterial uptake by phagocytes. Inhibition of metalloproteinase activity led to increased phagocytosis of pHrodo labelled Gram-negative and -positive bacteria (E. coli and S. aureus, respectively) by human and murine monocytic cell lines or primary phagocytes. Bone marrow-derived macrophages showed enhanced uptake of heat-inactivated and living E. coli when they lacked either ADAM17 or iRhom2 but not upon ADAM10-deficiency. In monocytic THP-1 cells, corresponding short hairpin RNA (shRNA)-mediated knockdown confirmed that ADAM17, but not ADAM10, promoted phagocytosis of E. coli. The augmented bacterial uptake occurred in a cell autonomous manner and was accompanied by increased release of the chemokine CXCL8, less TNFα release and only minimal changes in the surface expression of the receptors TNFR1, TLR6 and CD36. Inhibition experiments indicated that the enhanced bacterial phagocytosis after ADAM17 knockdown was partially dependent on TNFα-activity but not on CXCL8. This novel role of ADAM17 in bacterial uptake needs to be considered in the development of ADAM17 inhibitors as therapeutics.

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“…Thus, it is necessary to identify a new way to improve the EPCs function in CAD patients and reduce the occurrence of CVDs. Shear stress is a measure of nonpharmacological intervention which benefits the vascular endothelial homeostasis [17][18][19]. Nonetheless, the underlying mechanism by which shear stress affects the CAD-EPCs at the molecular level remains unclear so far.…”

Section: Introductionmentioning

confidence: 99%

Shear stress improves the endothelial progenitor cell function via the CXCR7/ERK pathway axis in the coronary artery disease cases

Zhou

Zhang

et al. 2020

BMC Cardiovasc Disord

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Background Dysfunction in the late Endothelial Progenitor Cells (EPCs) is responsible for endothelial repair in patients with Coronary Artery Disease (CAD), and the shear stress is beneficial for EPCs function. However, the impact of shear stress on the capacity of EPCs in CAD patients has not been elucidated yet. The C-X-C chemokine receptor 7/extracellular signal-regulated kinase (CXCR7)/(ERK) pathways are identified to regulate EPCs function in CAD patients. Here, we hypothesize that shear stress upregulates the CXCR7/ERK pathways, which restore the EPCs function in CAD patients. Methods The human Peripheral Blood Mononuclear Cells (PBMCs) were collected from healthy adults and CAD patients and then used for EPCs cultivation. The Lv-siRNA for human CXCR7 was transfected into induced EPCs isolated from the CAD patients. Meanwhile, the EPCs from CAD patients were subjected to shear stress generated by a biomimetic device. Next, the cell viability, migration, tube formation, and apoptosis were detected by CCK-8, Transwell assay, Matrigel, and flow cytometry, respectively. Also, the CXCR7/ERK pathways in human EPCs were analyzed by Western blotting and qRT-PCR. Result Compared to the EPCs collected from normal adults, the CAD patient-derived EPCs showed reduced in vitro vasculogenic capacity. Also, the level of CXCR7 in CAD patient-derived EPCs was significantly reduced compared to the EPCs of healthy subjects. Meanwhile, the extracellular signal-regulated kinase (ERK), which represents a CXCR7 downstream signaling pathway, had decreased phosphorylation level. The shear stress treatment augmented the CXCR7 expression and also elevated ERK phosphorylation, which is comparable to the up-regulation of CAD patient-derived EPCs function. Further, the small interfering RNA (siRNA)-mediated CXCR7 knockdown diminished the enhanced migration, adhesion, and tube formation capacity of shear stress treated CAD patient-derived EPCs. Conclusion Up-regulation of the CXCR7/ERK pathways by shear stress can be a promising new target in enhancing the vasculogenic ability of CAD patient-derived EPCs.

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The metalloproteinase ADAM15 is upregulated by shear stress and promotes survival of endothelial cells

Cited by 22 publications

References 46 publications

Flow-Induced Transcriptomic Remodeling of Endothelial Cells Derived From Human Induced Pluripotent Stem Cells

Flow-Induced Transcriptomic Remodeling of Endothelial Cells Derived From Human Induced Pluripotent Stem Cells

The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner

Shear stress improves the endothelial progenitor cell function via the CXCR7/ERK pathway axis in the coronary artery disease cases

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