Physiological role of the sarcolemmal calcium pump in the cardiovascular system – Characterization by gene-targeting ("knock-out")
Project management at the University of Würzburg:
- Prof. Dr. med. Ludwig Neyses
, Medizinische Universitätsklinik bis 31.07.2001
- Dr. med. Theo Pelzer
, Medizinische Universitätsklinik, Kardiologie, Josef-Schneider-Str. 2, 97080 Würzburg,Tel: 0931-201-36112,Fax: 0931-201-36151,Mail: firstname.lastname@example.org
- Dr. rer. nat. Kai Schuh
, Medizinische Universitätsklinik, AG Neyses, Josef-Schneider-Str. 2, 97080 Würzburg,Tel: 0931-201-36112,Fax: 0931-201-36151,Mail: email@example.com
Anomalies of intracellular calcium and signal transduction pathways play a pivotal role in the development of heart hypertrophy and failure.
The plasma membrane calmodulin-dependent Ca2+ ATPase (PMCA) transports Ca2+ from the cytosol to the extracellular milieu. Its physiological function, however, especially in myocardium and smooth muscle, is unknown. So far, two major hypotheses exist: It is either a co-regulator of contraction/relaxation cycle in the myocardium or, alternatively, a regulator of long-term Ca2+-dependent signal transduction pathways.
We demonstrated in PMCA-overexpression models (in the myocardium of transgenic rats as well as L6-myoblasts) that PMCA is co-localized in caveolae with a variety of proteins involved in signal transduction, (such as eNOS, Gs alpha, caveolin-3, PDGF BB receptor, ras), that the PMCA interacts physically with some of these proteins and that overexpression is accompanied by an enhanced protein synthesis rate in response to various stimuli. No changes in the baseline or peak contractile performance of the transgenic rat hearts were observed. These findings strongly suggest an involvement of PMCA in caveolae-mediated signal transduction but not in beat-to-beat regulation of the heart muscle.
To define the (patho-) physiological mechanisms regulated by PMCA activity in the cardiovascular system we are in the process of establishing conventional and tissue specific PMCA 4- and PMCA1-deficient mice and other transgenic models. In particular, the function of PMCA 4 / and 1 in physiological and pathological signal transduction processes (see above) will be investigated. Additionally, the development of these animals as well as the cellular integrity (key words: dystrophin, cytoskeleton) will be part of the investigation.
from 01.1999 to 12.2001
DFG ,Granting date: 02.12.1998
- Pelzer, T., de Jager, T., Muck, J., Stimpel, M., Neyses, L..
(2002). Oestrogen action on the myocardium in vivo: specific and permissive for angiotensin-converting enzyme inhibition. (monograph)
- Ritter, O., Hack, S., Schuh, K., Roethlein, N., Perrot, A., Osterziel, K. J., Schulte, H. D., and Neyses, L..
(2002). Calcineurin in human heart hypertrophy. (monograph)
- Schuh, K., Uldrijan, S., Telkamp, M., Rothlein, N., and Neyses, L..
(2001). The plasmamembrane calmodulin-dependent calcium pump: a major regulator of nitric oxide synthase I. (monograph)
- Pelzer, T., Neumann, M., de Jager, T., Jazbutyte, V., Neyses, L.
(2001). Estrogen effects in the myocardium: inhibition of NF-kappaB DNA binding by estrogen receptor-alpha and -beta. (monograph)
- de Jager, T., Pelzer, T., Muller-Botz, S., Imam, A., Muck, J., Neyses L.:.
(2001). Mechanisms of estrogen receptor action in the myocardium. Rapid gene activation via the ERK1/2 pathway and serum response elements. (monograph)
- Piuhola, J., Hammes, A., Schuh, K., Neyses, L., Vuolteenaho, O., and Ruskoaho, H.:.
(2001). Overexpression of sarcolemmal calcium pump attenuates induction of cardiac gene expression in response to ET-1. (monograph)
- Pelzer, T., Schumann, M., Neumann, M., deJager, T., Stimpel, M., Serfling, E., Neyses L.:.
(2000). 17beta-estradiol prevents programmed cell death in cardiac myocytes. (monograph)
- Shamim, A., Pelzer, T., Grohe, C., Neyses, L..
(1999). Induction of Egr-1 mRNA and protein by endothelin 1, angiotensin II and norepinephrine in neonatal cardiac myocytes. (monograph)
- Benkwitz, C., Oberdorf-Maass, S., and Neyses, L..
(1999). Combined SSCP and Heteroduplex Analysis of the Human Plasma Membrane Ca2+-ATPase Isoform 1 in Patients with Essential Hypertension. (monograph)
University Hospital Würzburg