@article{AueEnglertHarreretal.2023, author = {Aue, Annemarie and Englert, Nils and Harrer, Leon and Schwiering, Fabian and Gaab, Annika and K{\"o}nig, Peter and Adams, Ralf and Schmidtko, Achim and Friebe, Andreas and Groneberg, Dieter}, title = {NO-sensitive guanylyl cyclase discriminates pericyte-derived interstitial from intra-alveolar myofibroblasts in murine pulmonary fibrosis}, series = {Respiratory Research}, volume = {24}, journal = {Respiratory Research}, doi = {10.1186/s12931-023-02479-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357805}, year = {2023}, abstract = {Background The origin of αSMA-positive myofibroblasts, key players within organ fibrosis, is still not fully elucidated. Pericytes have been discussed as myofibroblast progenitors in several organs including the lung. Methods Using tamoxifen-inducible PDGFRβ-tdTomato mice (PDGFRβ-CreERT2; R26tdTomato) lineage of lung pericytes was traced. To induce lung fibrosis, a single orotracheal dose of bleomycin was given. Lung tissue was investigated by immunofluorescence analyses, hydroxyproline collagen assay and RT-qPCR. Results Lineage tracing combined with immunofluorescence for nitric oxide-sensitive guanylyl cyclase (NO-GC) as marker for PDGFRβ-positive pericytes allows differentiating two types of αSMA-expressing myofibroblasts in murine pulmonary fibrosis: (1) interstitial myofibroblasts that localize in the alveolar wall, derive from PDGFRβ+ pericytes, express NO-GC and produce collagen 1. (2) intra-alveolar myofibroblasts which do not derive from pericytes (but express PDGFRβ de novo after injury), are negative for NO-GC, have a large multipolar shape and appear to spread over several alveoli within the injured areas. Moreover, NO-GC expression is reduced during fibrosis, i.e., after pericyte-to-myofibroblast transition. Conclusion In summary, αSMA/PDGFRβ-positive myofibroblasts should not be addressed as a homogeneous target cell type within pulmonary fibrosis.}, language = {en} } @article{KorkmazPuladiGalleretal.2021, author = {Korkmaz, Y{\"u}ksel and Puladi, Behrus and Galler, Kerstin and K{\"a}mmerer, Peer W. and Schr{\"o}der, Agnes and G{\"o}lz, Lina and Sparwasser, Tim and Bloch, Wilhelm and Friebe, Andreas and Deschner, James}, title = {Inflammation in the human periodontium induces downregulation of the α\(_1\)- and β\(_1\)-subunits of the sGC in cementoclasts}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms22020539}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285783}, year = {2021}, abstract = {Nitric oxide (NO) binds to soluble guanylyl cyclase (sGC), activates it in a reduced oxidized heme iron state, and generates cyclic Guanosine Monophosphate (cGMP), which results in vasodilatation and inhibition of osteoclast activity. In inflammation, sGC is oxidized and becomes insensitive to NO. NO- and heme-independent activation of sGC requires protein expression of the α\(_1\)- and β\(_1\)-subunits. Inflammation of the periodontium induces the resorption of cementum by cementoclasts and the resorption of the alveolar bone by osteoclasts, which can lead to tooth loss. As the presence of sGC in cementoclasts is unknown, we investigated the α\(_1\)- and β\(_1\)-subunits of sGC in cementoclasts of healthy and inflamed human periodontium using double immunostaining for CD68 and cathepsin K and compared the findings with those of osteoclasts from the same sections. In comparison to cementoclasts in the healthy periodontium, cementoclasts under inflammatory conditions showed a decreased staining intensity for both α\(_1\)- and β\(_1\)-subunits of sGC, indicating reduced protein expression of these subunits. Therefore, pharmacological activation of sGC in inflamed periodontal tissues in an NO- and heme-independent manner could be considered as a new treatment strategy to inhibit cementum resorption.}, language = {en} } @article{GambaryanSubramanianKehreretal.2016, author = {Gambaryan, Stepan and Subramanian, Hariharan and Kehrer, Linda and Mindukshev, Igor and Sudnitsyna, Julia and Reiss, Cora and Rukoyatkina, Natalia and Friebe, Andreas and Sharina, Iraida and Martin, Emil and Walter, Ulrich}, title = {Erythrocytes do not activate purified and platelet soluble guanylate cyclases even in conditions favourable for NO synthesis}, series = {Cell Communication and Signaling}, volume = {14}, journal = {Cell Communication and Signaling}, number = {16}, doi = {10.1186/s12964-016-0139-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161223}, year = {2016}, abstract = {Background Direct interaction between Red blood cells (RBCs) and platelets is known for a long time. The bleeding time is prolonged in anemic patients independent of their platelet count and could be corrected by transfusion of RBCs, which indicates that RBCs play an important role in hemostasis and platelet activation. However, in the last few years, opposing mechanisms of platelet inhibition by RBCs derived nitric oxide (NO) were proposed. The aim of our study was to identify whether RBCs could produce NO and activate soluble guanylate cyclase (sGC) in platelets. Methods To test whether RBCs could activate sGC under different conditions (whole blood, under hypoxia, or even loaded with NO), we used our well-established and highly sensitive models of NO-dependent sGC activation in platelets and activation of purified sGC. The activation of sGC was monitored by detecting the phosphorylation of Vasodilator Stimulated Phosphoprotein (VASPS239) by flow cytometry and Western blot. ANOVA followed by Bonferroni's test and Student's t-test were used as appropriate. Results We show that in the whole blood, RBCs prevent NO-mediated inhibition of ADP and TRAP6-induced platelet activation. Likewise, coincubation of RBCs with platelets results in strong inhibition of NO-induced sGC activation. Under hypoxic conditions, incubation of RBCs with NO donor leads to Hb-NO formation which inhibits sGC activation in platelets. Similarly, RBCs inhibit activation of purified sGC, even under conditions optimal for RBC-mediated generation of NO from nitrite. Conclusions All our experiments demonstrate that RBCs act as strong NO scavengers and prevent NO-mediated inhibition of activated platelets. In all tested conditions, RBCs were not able to activate platelet or purified sGC.}, language = {en} } @article{HoffmannEtzrodtWillkommetal.2015, author = {Hoffmann, Linda S. and Etzrodt, Jennifer and Willkomm, Lena and Sanyal, Abhishek and Scheja, Ludger and Fischer, Alexander W. C. and Stasch, Johannes-Peter and Bloch, Wilhelm and Friebe, Andreas and Heeren, Joerg and Pfeifer, Alexander}, title = {Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue}, series = {Nature Communications}, volume = {6}, journal = {Nature Communications}, number = {7235}, doi = {10.1038/ncomms8235}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143127}, year = {2015}, abstract = {Obesity is characterized by a positive energy balance and expansion of white adipose tissue (WAT). In contrast, brown adipose tissue (BAT) combusts energy to produce heat. Here we show that a small molecule stimulator (BAY 41-8543) of soluble guanylyl cyclase (sGC), which produces the second messenger cyclic GMP (cGMP), protects against diet-induced weight gain, induces weight loss in established obesity, and also improves the diabetic phenotype. Mechanistically, the haeme-dependent sGC stimulator BAY 41-8543 enhances lipid uptake into BAT and increases whole-body energy expenditure, whereas ablation of the haeme-containing \(\beta\)\(_{1}\)-subunit of sGC severely impairs BAT function. Notably, the sGC stimulator enhances differentiation of human brown adipocytes as well as induces 'browning' of primary white adipocytes. Taken together, our data suggest that sGC is a potential pharmacological target for the treatment of obesity and its comorbidities.}, language = {en} }