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802 results on '"Hammes, Hans-Peter"'

17. Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy

Author

Hu, Jiong, Dziumbla, Sarah, Lin, Jihong, Bibli, Sofia-Iris, Zukunft, Sven, de Mos, Julian, Awwad, Khader, Frömel, Timo, Jungmann, Andreas, Devraj, Kavi, Cheng, Zhixing, Wang, Liya, Fauser, Sascha, Eberhart, Charles G, Sodhi, Akrit, Hammock, Bruce D, Liebner, Stefan, Müller, Oliver J, Glaubitz, Clemens, Hammes, Hans-Peter, Popp, Rüdiger, and Fleming, Ingrid

Subjects
Biomedical and Clinical Sciences, Ophthalmology and Optometry, Diabetes, Eye Disease and Disorders of Vision, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Metabolic and endocrine, Animals, Antigens, CD, Cadherins, Capillary Permeability, Carrier Proteins, Cell Membrane, Cell Movement, Cell Survival, Diabetic Retinopathy, Disease Models, Animal, Disease Progression, Docosahexaenoic Acids, Endothelial Cells, Ependymoglial Cells, Epoxide Hydrolases, Fatty Acids, Unsaturated, Female, Humans, Intercellular Junctions, Male, Mice, Mice, Inbred C57BL, Pancreatic Elastase, Pericytes, Presenilin-1, Retina, Solubility, Vitreous Body, General Science & Technology
Abstract

Diabetic retinopathy is an important cause of blindness in adults, and is characterized by progressive loss of vascular cells and slow dissolution of inter-vascular junctions, which result in vascular leakage and retinal oedema. Later stages of the disease are characterized by inflammatory cell infiltration, tissue destruction and neovascularization. Here we identify soluble epoxide hydrolase (sEH) as a key enzyme that initiates pericyte loss and breakdown of endothelial barrier function by generating the diol 19,20-dihydroxydocosapentaenoic acid, derived from docosahexaenoic acid. The expression of sEH and the accumulation of 19,20-dihydroxydocosapentaenoic acid were increased in diabetic mouse retinas and in the retinas and vitreous humour of patients with diabetes. Mechanistically, the diol targeted the cell membrane to alter the localization of cholesterol-binding proteins, and prevented the association of presenilin 1 with N-cadherin and VE-cadherin, thereby compromising pericyte-endothelial cell interactions and inter-endothelial cell junctions. Treating diabetic mice with a specific sEH inhibitor prevented the pericyte loss and vascular permeability that are characteristic of non-proliferative diabetic retinopathy. Conversely, overexpression of sEH in the retinal Müller glial cells of non-diabetic mice resulted in similar vessel abnormalities to those seen in diabetic mice with retinopathy. Thus, increased expression of sEH is a key determinant in the pathogenesis of diabetic retinopathy, and inhibition of sEH can prevent progression of the disease.

Published
2017

28. Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity

Author

Hu, Jiong, Bibli, Sofia-Iris, Wittig, Janina, Zukunft, Sven, Lin, Jihong, Hammes, Hans-Peter, Popp, Rudiger, and Fleming, Ingrid

Subjects
Thermo Fisher Scientific Inc., Prevention, Physiological aspects, Nitration -- Physiological aspects, Hydrolases -- Physiological aspects, Omega 3 fatty acids -- Physiological aspects, Unsaturated fatty acids -- Physiological aspects, Tyrosine -- Physiological aspects, Childhood vision disorders -- Prevention -- Physiological aspects, Dietary supplements -- Physiological aspects, Mitochondrial DNA -- Physiological aspects, Scientific equipment industry -- Physiological aspects, Retinopathy of prematurity -- Prevention -- Physiological aspects, Infants, Phenols (Class of compounds), DNA, DNA damage, Fatty acids, Monosaccharides, Enzymes, Glycols (Class of compounds)
Abstract

Introduction Retinopathy of prematurity (ROP) is a complication of treating preterm infants with [O.sub.2]. It is estimated that as many as 10% of very premature infants become blind as a [...], Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) positively affect the outcome of retinopathy of prematurity (ROP). Given that DHA metabolism by cytochrome P450 and soluble epoxide hydrolase (sEH) enzymes affects retinal angiogenesis and vascular stability, we investigated the role of sEH in a mouse model of ROP. In WT mice, hyperoxia elicited tyrosine nitration and inhibition of sEH and decreased generation of the DHA-derived diol 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP). Correspondingly, in a murine model of ROP, [sEH.sup.-/-] mice developed a larger central a vascular zone and peripheral pathological vascular tuft formation than did their WT littermates. Astrocytes were the cells most affected by Seh deletion, and hyperoxia increased astrocyte apoptosis. In rescue experiments, 19,20-DHDP prevented astrocyte loss by targeting the mitochondrial membrane to prevent the hyperoxia-induced dissociation of presenilin-1 and presenilin-1-associated protein to attenuate poly ADP-ribose polymerase activation and mitochondrial DNA damage. Therapeutic intravitreal administration of 19,20-DHDP not only suppressed astrocyte loss, but also reduced pathological vascular tuft formation in [sEH.sup.-/-] mice. Our data indicate that sEH activity is required for mitochondrial integrity and retinal astrocyte survival in ROP. Moreover, 19,20-DHDP may be more effective than DHA as a nutritional supplement for preventing retinopathy in preterm infants.

Published
2019
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33. In VivoOptogenetic Manipulation of Transgene Expression in Retinal Neurovasculature

Author

Brandhorst, Eric, Xu, Liang, Klimezak, Maxime, Goegan, Bastien, Hong, Huixiao, Hammes, Hans-Peter, Specht, Alexandre, and Cambridge, Sidney

Abstract

The retina is prone to developing pathological neovascularization, a leading cause of blindness in humans. Because excess neovascularization does not affect the entire retina, global inhibition treatment of angiogenesis critically interferes with healthy, unaffected retinal tissue. We therefore established an in vivophotoactivated gene expression paradigm which would allow light-mediated targeting of antiangiogenic genetic treatment only to affected retinal regions. We synthesized a “caged” (i.e., reversibly inhibited) photosensitive 4-hydroxytamoxifen analog. Molecular docking analyses validated its reduced transcriptional activity. Caged 4-hydroxytamoxifen was intravitreally injected into mice harboring the inducible Cre/lox system, with CreERT2 being expressed viathe Tie2 promoter in the neurovasculature. Subsequent in vivoirradiation of eyes significantly induced retinal expression of a Cre-dependent transgene in retinal blood vessels. Using GFAP-CreERT2 mice, successful photoactivation was also achieved in eyes and also in ex vivobrain slices for validation of the approach. This highlights the possibility of light-mediated gene therapies specific for the retina, a key first step in personalized medicine.

Published
2024
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34. A Hepatic GAbp-AMPK Axis Links Inflammatory Signaling to Systemic Vascular Damage

Author

Niopek, Katharina, Üstünel, Bilgen Ekim, Seitz, Susanne, Sakurai, Minako, Zota, Annika, Mattijssen, Frits, Wang, Xiaoyue, Sijmonsma, Tjeerd, Feuchter, Yvonne, Gail, Anna M., Leuchs, Barbara, Niopek, Dominik, Staufer, Oskar, Brune, Maik, Sticht, Carsten, Gretz, Norbert, Müller-Decker, Karin, Hammes, Hans-Peter, Nawroth, Peter, Fleming, Thomas, Conkright, Michael D., Blüher, Matthias, Zeigerer, Anja, Herzig, Stephan, and Berriel Diaz, Mauricio

Published
2017
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44. Impaired Retinal Vessel Dilation Predicts Mortality in End-Stage Renal Disease

Author

Günthner, Roman, Hanssen, Henner, Hauser, Christine, Angermann, Susanne, Lorenz, Georg, Kemmner, Stephan, Matschkal, Julia, Braunisch, Matthias C., Küchle, Claudius, Renders, Lutz, Moog, Philipp, Wassertheurer, Siegfried, Baumann, Marcus, Hammes, Hans-Peter, Mayer, Christopher C., Haller, Bernhard, Stryeck, Sarah, Madl, Tobias, Carbajo-Lozoya, Javier, Heemann, Uwe, Kotliar, Konstantin, and Schmaderer, Christoph

Published
2019
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