期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：1997
卷号：94
期号：22
页码：12100-12105
DOI：10.1073/pnas.94.22.12100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. Our laboratory has been focusing on the feasibility of restoring {beta}-adrenergic signaling deficiencies that are a characteristic of chronic CHF. We have now studied isolated ventricular myocytes from rabbits that have been chronically paced to produce hemodynamic failure. We document molecular {beta}-adrenergic signaling defects including down-regulation of myocardial {beta}-adrenergic receptors ({beta}-ARs), functional {beta}-AR uncoupling, and an up-regulation of the {beta}-AR kinase ({beta}ARK1). Adenoviral-mediated gene transfer of the human {beta}2-AR or an inhibitor of {beta}ARK1 to these failing myocytes led to the restoration of {beta}-AR signaling. These results demonstrate that defects present in this critical myocardial signaling pathway can be corrected in vitro using genetic modification and raise the possibility of novel inotropic therapies for CHF including the inhibition of {beta}ARK1 activity in the heart.
