@article{HoffmannSchmidtKeimetal.2011,
  author    = {Hoffmann, Linda S and Schmidt, Peter M and Keim, Yvonne and Hoffmann, Carsten and Schmidt, Harald H H W and Stasch, Johannes-Peter},
  title     = {Fluorescence Dequenching Makes Haem-Free Soluble Guanylate Cyclase Detectable in Living Cells},
  series = {PLOS ONE},
  volume    = {6},
  journal   = {PLOS ONE},
  number    = {8},
  doi       = {10.1371/journal.pone.0023596},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139631},
  pages     = {e23596},
  year      = {2011},
  abstract  = {In cardiovascular disease, the protective NO/sGC/cGMP signalling-pathway is impaired due to a decreased pool of NO-sensitive haem-containing sGC accompanied by a reciprocal increase in NO-insensitive haem-free sGC. However, no direct method to detect cellular haem-free sGC other than its activation by the new therapeutic class of haem mimetics, such as BAY 58-2667, is available. Here we show that fluorescence dequenching, based on the interaction of the optical active prosthetic haem group and the attached biarsenical fluorophor FlAsH can be used to detect changes in cellular sGC haem status. The partly overlap of the emission spectrum of haem and FlAsH allows energy transfer from the fluorophore to the haem which reduces the intensity of FlAsH fluorescence. Loss of the prosthetic group, e. g. by oxidative stress or by replacement with the haem mimetic BAY 58-2667, prevented the energy transfer resulting in increased fluorescence. Haem loss was corroborated by an observed decrease in NO-induced sGC activity, reduced sGC protein levels, and an increased effect of BAY 58-2667. The use of a haem-free sGC mutant and a biarsenical dye that was not quenched by haem as controls further validated that the increase in fluorescence was due to the loss of the prosthetic haem group. The present approach is based on the cellular expression of an engineered sGC variant limiting is applicability to recombinant expression systems. Nevertheless, it allows to monitor sGC's redox regulation in living cells and future enhancements might be able to extend this approach to in vivo conditions.},
  language  = {en}
}
@article{IyengarSedorFreedmanetal.2015,
  author    = {Iyengar, Sudha K. and Sedor, John R. and Freedman, Barry I. and Kao, W. H. Linda and Kretzler, Matthias and Keller, Benjamin J. and Abboud, Hanna E. and Adler, Sharon G. and Best, Lyle G. and Bowden, Donald W. and Burlock, Allison and Chen, Yii-Der Ida and Cole, Shelley A. and Comeau, Mary E. and Curtis, Jeffrey M. and Divers, Jasmin and Drechsler, Christiane and Duggirala, Ravi and Elston, Robert C. and Guo, Xiuqing and Huang, Huateng and Hoffmann, Michael Marcus and Howard, Barbara V. and Ipp, Eli and Kimmel, Paul L. and Klag, Michael J. and Knowler, William C. and Kohn, Orly F. and Leak, Tennille S. and Leehey, David J. and Li, Man and Malhotra, Alka and M{\"a}rz, Winfried and Nair, Viji and Nelson, Robert G. and Nicholas, Susanne B. and O'Brien, Stephen J. and Pahl, Madeleine V. and Parekh, Rulan S. and Pezzolesi, Marcus G. and Rasooly, Rebekah S. and Rotimi, Charles N. and Rotter, Jerome I. and Schelling, Jeffrey R. and Seldin, Michael F. and Shah, Vallabh O. and Smiles, Adam M. and Smith, Michael W. and Taylor, Kent D. and Thameem, Farook and Thornley-Brown, Denyse P. and Truitt, Barbara J. and Wanner, Christoph and Weil, E. Jennifer and Winkler, Cheryl A. and Zager, Philip G. and Igo, Jr, Robert P. and Hanson, Robert L. and Langefeld, Carl D.},
  title     = {Genome-wide association and trans-ethnic meta-analysis for advanced diabetic kidney disease: Family Investigation of Nephropathy and Diabetes (FIND)},
  series = {PLoS Genetics},
  volume    = {11},
  journal   = {PLoS Genetics},
  number    = {8},
  doi       = {10.1371/journal.pgen.1005352},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-180545},
  pages     = {e1005352},
  year      = {2015},
  abstract  = {Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45\% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10\(^{-9}\)). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10\(^{-8}\)), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.},
  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}
}