Wunderlich Carsten, Schober Kristin, Lange Stefan A, Drab Marek, Braun-Dullaeus Ruediger C, Kasper Michael, Schwencke Carsten, Schmeisser Alexander, Strasser Ruth H
University of Technology Dresden, Department of Cardiology, Medical Clinic, Fetscherstr. 76, D-01307 Dresden, Germany.
Biochem Biophys Res Commun. 2006 Feb 10;340(2):702-8. doi: 10.1016/j.bbrc.2005.12.058. Epub 2005 Dec 20.
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.
尽管小窝蛋白-1在心肌细胞中不表达，但该蛋白被认为在心肌病的发展中起关键调节作用。鉴于最近不一致的研究结果，我们旨在阐明独立产生的小窝蛋白-1基因敲除小鼠（cav-1(-/-)）的心脏表型，并揭示其致病机制。对cav-1(-/-)小鼠进行的有创血流动力学测量显示，其收缩期和舒张期心脏功能严重降低。此外，小窝蛋白-1的基因缺失导致显著的双心室肥厚和持续的内皮型一氧化氮合酶过度激活，从而使全身一氧化氮水平升高。此外，还测量了基因敲除动物心脏中ATP含量的减少和环磷酸腺苷水平的降低。综上所述，这些结果表明，小窝蛋白-1的基因破坏足以诱导严重的双心室肥厚，并伴有收缩期和舒张期心力衰竭的迹象。总体而言，我们的研究结果表明，持续的亚硝化应激在明显的心脏损伤发展中起致病作用。
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