Die Rolle von "transient receptor potential (TRP)"-Kanälen bei der Hypoxie-induzierten pulmonalen Hypertonie und beim vaskulären Gefäßumbau
Final Report Abstract
The overall aim of this project was to understand TRPC function in acute, prolonged and chronic hypoxia-induced pulmonary hypertension (HPH). We identified TRPC1 as important channel for promoting chronic HPH and vascular remodeling by analyzing a TRPC1-/- mouse model. TRPC1 is responsible for proliferation of precapillary pulmonary arterial smooth muscle cells (PASMC) and muscularization of small arterial vessels which is essential for the development of HPH. Therefore, TRPC1 is next to TRPC6 which is responsible for acute HPH the second TRPC channel involved in lung vascular abnormalities developing under conditions of hypoxia. We set out to dissect pathways leading to TRPC activation in PASMC by establishing specific siRNAs directed against proteins possibly involved in these signal transduction cascades. Novel proteins responsible for TRPC activation in HPH will be detected by successful inhibition of hypoxia-induced TRPC activity identified by patch clamp recordings in PASMC transfected with specific siRNAs. In a third approach we evaluated a microarray-based screening method to identify genes differentially regulated by Ca2+ influx after hypoxia through TRPC channels in PASMC. We used wild-type and TRPC1-/- PASMC under normoxic and hypoxic conditions to detect genes regulated by hypoxia and TRPC1 gene ablation. A more detailed analysis of the identified genes is currently performed in our laboratories. In all three approaches novel pharmacological targets are already identified and we are convinced that they will be helpful to develop a therapeutic intervention for HPH.
Publications
- (2011). Diacylglycerol regulates acute hypoxic pulmonary vasoconstriction via TRPC6. Resp. Res. 12: 20
Fuchs, B., Rupp, M., Ghofrani, H.A., Schermuly, R.T., Seeger, W., Grimminger, F., Gudermann, T., Dietrich, A., Weissmann, N.
- (2012). Activation of TRPC6 channels is essential for ischemia–reperfusion-induced lung edema in mice. Nature Commun. 3: 649
Weissmann, N., Sydykov, A., Kalwa, H., Storch, U., Fuchs, B., Mederos y Schnitzler, M., Brandes, R.P., Grimminger, F., Meissner, M., Freichel, M., Offermanns, S., Veit, F., Pak, O., Krause, K.-H., Schermuly, R.T., Brewer, A.C., Schmidt, H.H.H.W., Seeger, W., Shah, A.M., Gudermann, T., Ghofrani, H.A. & Dietrich, A.
- (2012). Lung endothelial Ca2+ and permeability response to PAF is mediated by acid sphingomyelinase and TRPC6. Am. J. Resp. Crit. Care. 185: 160-170
Samapati, R. Yang, Y., Yin, J., Stoergers, C., Arenz, C., Dietrich, A., Gudermann, T., Adams, D., Wu, S., Freichel, M., Flockerzi, V., Uhlig, S., Kuebler, W.M.
(See online at https://doi.org/10.1164/rccm.201104-0717OC) - (2012). TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation. J. Exp. Med. 209: 1953-1968
Tauseef M., Knezevic N., Chava K.R., Smith M., Sukriti S., Gianaris N., Obukhov A.G., Vogel S.M., Schraufnagel D.E., Dietrich A., Birnbaumer L., Malik A.B., Mehta D.
(See online at https://doi.org/10.1084/jem.20111355)
