Clin Res Cardiol 100, Suppl 1, April 2011

P646 - Genetic loss of eNOS restores cardiopulmonary function of Caveolin-1 knockout mice - insights from a double knockout mouse
 
N. Steinbronn1, A. Brandt1, J. Lehmann1, S. Weinert2, R. Marquetant1, R. Braun-Dullaeus2, R. H. Strasser1, C. Wunderlich1
 
1Klinik für Innere Medizin, Kardiologie und Intensivmedizin, TU Universität Dresden, Herzzentrum Dresden Universitätsklinik, Dresden; 2Klinik für Kardiologie, Angiologie und Pneumologie, Universitätsklinikum Magdeburg, Magdeburg;
 
Previous results of our group indicate that Caveolin-1 knockout mice (cav1-ko) show an adverse cardiopulmonary phenotype with signs of severe systolic and diastolic heart failure and lung fibrosis. Data using tetrahydrobiopterin to recouple endothelial nitric oxide suggest that an increased production of reactive oxygen species via an uncoupled endothelial nitric oxide synthase (eNOS) plays a pivotal role. To establish the causal role of eNOS in the development of the cardiopulmonary pathology of cav1-ko newly generated Caveolin-1/eNOS double knockout mice (cav1/eNOS-ko) were investigated.
Cav1/eNOS-ko were generated by crossbreeding eNOS- and cav1-ko. Their offspring is viable but litters are reduced to one third (4 +/-1) as compared to wildtype (WT) (11 +/-2). The bodyweight of cav1/eNOS-ko is markedly reduced compared to all other strains, however the overall lifespan is comparable to that of eNOS- or cav1-ko.
Echocardiographic investigations and invasive hemodynamic measurements using a pressure volume catheter documented the improved cardiac performance of cav1/eNOS-ko compared to cav1-ko. The double knockouts displayed a significantly improved left ventricular systolic function (LV developed pressure and dP/dtmax) as compared to cav1-ko. Additionally, marked improvements of the diastolic heart function were evident in cav1/eNOS-ko. Notably, systolic and diastolic heart function almost reached WT level (cav1/eNOS-ko: dP/dtmax: 7891 +/- 324 mmHg/s; dP/dtmin: -7921 +/- 287, cav1-ko: dP/dtmax: 5288 +/- 300 mmHg/s; dP/dtmin: -4692 +/- 305; WT: dP/dtmax: 10227 +/- 904 mmHg/s; dP/dtmin: -9053 +/- 882). The restored cardiac performance was accompanied by an enhanced physical competence of cav1/eNOS-ko as shown in swimming chamber tests in comparison to cav1-ko. Furthermore, microscopic analysis of heart and lung tissue revealed a normalized heart and lung architecture in cav1/eNOS-ko.
Both the echocardiographic and the invasive data show that the loss of eNOS prevents the pathological development of the cardiopulmonary phenotype of cav1-ko. Whether the same holds true in human cardiomyopathy is focus of further ongoing studies.
 
Clin Res Cardiol 100, Suppl 1, April 2011
Zitierung mit Vortrags- oder Posternummer s.o.
DOI 10.1007/s00392-011-1100-y

http://www.abstractserver.de/dgk2011/ft/abstracts/P646.htm