Disruption of caveolin-1 leads to enhanced nitrosative stress and severe systolic and diastolic heart failure.
Although caveolin-1 is not expressed in cardiomyocytes, this protein is assumed to act as a key regulator in the development of cardiomyopathy. In view of recent discordant findings we aimed to elucidate the cardiac phenotype of independently generated caveolin-1 knockout mice (cav-1(-/-)) and to unveil causative mechanisms. Invasive hemodynamic measurements of cav-1(-/-) show a severely reduced systolic and diastolic heart function. Additionally, genetic ablation of caveolin-1 leads to a striking biventricular hypertrophy and to a sustained eNOS-hyperactivation yielding increased systemic NO levels. Furthermore, a diminished ATP content and reduced levels of cyclic AMP in hearts of knockout animals were measured. Taken together, these results indicate that genetic disruption of caveolin-1 is sufficient to induce a severe biventricular hypertrophy with signs of systolic and diastolic heart failure. Collectively, our findings suggest a causative role of a sustained nitrosative stress in the development of the pronounced cardiac impairment.
Wunderlich
Carsten
C
University of Technology Dresden, Department of Cardiology, Medical Clinic, Fetscherstr. 76, D-01307 Dresden, Germany. carstenwunderlich@gmx.de
Schober
Kristin
K
Lange
Stefan A
SA
Drab
Marek
M
Braun-Dullaeus
Ruediger C
RC
Kasper
Michael
M
Schwencke
Carsten
C
Schmeisser
Alexander
A
Strasser
Ruth H
RH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051242:Caveolin 1 / Q000172:deficiency* / Q000235:genetics*; D000242:Cyclic AMP / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D012720:Severity of Illness Index
D051242:Caveolin 1; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse