White D C, Hata J A, Shah A S, Glower D D, Lefkowitz R J, Koch W J
Department of Surgery, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5428-33. doi: 10.1073/pnas.090091197.
When the heart fails, there is often a constellation of biochemical alterations of the beta-adrenergic receptor (betaAR) signaling system, leading to the loss of cardiac inotropic reserve. betaAR down-regulation and functional uncoupling are mediated through enhanced activity of the betaAR kinase (betaARK1), the expression of which is increased in ischemic and failing myocardium. These changes are widely viewed as representing an adaptive mechanism, which protects the heart against chronic activation. In this study, we demonstrate, using in vivo intracoronary adenoviral-mediated gene delivery of a peptide inhibitor of betaARK1 (betaARKct), that the desensitization and down-regulation of betaARs seen in the failing heart may actually be maladaptive. In a rabbit model of heart failure induced by myocardial infarction, which recapitulates the biochemical betaAR abnormalities seen in human heart failure, delivery of the betaARKct transgene at the time of myocardial infarction prevents the rise in betaARK1 activity and expression and thereby maintains betaAR density and signaling at normal levels. Rather than leading to deleterious effects, cardiac function is improved, and the development of heart failure is delayed. These results appear to challenge the notion that dampening of betaAR signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of betaARK1 and preservation of myocardial betaAR function.
当心脏衰竭时，β-肾上腺素能受体（βAR）信号系统常常会出现一系列生化改变，导致心脏变力储备丧失。βAR下调和功能解偶联是由βAR激酶（βARK1）活性增强介导的，其表达在缺血和衰竭心肌中增加。这些变化被广泛认为是一种适应性机制，可保护心脏免受慢性激活。在本研究中，我们通过体内冠状动脉内腺病毒介导的βARK1肽抑制剂（βARKct）基因递送证明，在衰竭心脏中看到的βAR脱敏和下调实际上可能是适应不良的。在由心肌梗死诱导的心力衰竭兔模型中，该模型重现了人类心力衰竭中出现的生化βAR异常，在心肌梗死时递送βARKct转基因可防止βARK1活性和表达升高，从而将βAR密度和信号维持在正常水平。心脏功能得到改善，而不是导致有害影响，并且心力衰竭的发展被延迟。这些结果似乎挑战了衰竭心脏中βAR信号减弱具有保护作用的观点，并且它们可能会导致通过抑制βARK1和保留心肌βAR功能来治疗心脏病的新治疗策略。
