Akhter S A, Skaer C A, Kypson A P, McDonald P H, Peppel K C, Glower D D, Lefkowitz R J, Koch W J
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 1997 Oct 28;94(22):12100-5. doi: 10.1073/pnas.94.22.12100.
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 (betaARK1). Adenoviral-mediated gene transfer of the human beta2-AR or an inhibitor of betaARK1 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 betaARK1 activity in the heart.
心血管基因治疗是一种治疗诸如充血性心力衰竭（CHF）等疾病的新方法。将基因导入心脏可实现对有缺陷或缺失的细胞蛋白的替代，这可能改善心脏功能。我们实验室一直专注于恢复慢性CHF所特有的β-肾上腺素能信号缺陷的可行性。我们现在研究了来自经长期起搏导致血流动力学衰竭的兔子的离体心室肌细胞。我们记录了分子β-肾上腺素能信号缺陷，包括心肌β-肾上腺素能受体（β-ARs）的下调、功能性β-AR解偶联以及β-AR激酶（βARK1）的上调。将人β2-AR或βARK1抑制剂通过腺病毒介导的基因转移导入这些衰竭的肌细胞，可使β-AR信号得以恢复。这些结果表明，通过基因修饰可在体外纠正这一关键心肌信号通路中存在的缺陷，并增加了针对CHF的新型正性肌力疗法的可能性，包括抑制心脏中的βARK1活性。
