Department of Pharmaceutical Sciences, Laboratory for the Study of Neurohormonal Control of the Circulation, Nova Southeastern University College of Pharmacy, Fort Lauderdale, FL 33328, USA.
Cell Commun Signal. 2013 Aug 28;11:64. doi: 10.1186/1478-811X-11-64.
β1- and β2-adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF).
We crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β2AR-dependent contractile function, as β2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of βARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac β2AR, which is normally mediated by the actions of GRK2 and βarrs on the receptor. The molecular "brake" that PDE4D poses on β2AR signaling to contractility stimulation is thus "released". Regarding the other beneficial functions of cardiac β2AR, βARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed.
GRK2 inhibition in vivo with βARKct is absolutely essential for cardiac β2AR pro-contractile signaling and function. In addition, β2AR anti-apoptotic signaling in post-MI HF is augmented by βARKct, although this effect is short-lived.
β1-和β2-肾上腺素能受体（ARs）在心脏中发挥不同的作用，例如β1AR 是促收缩和促凋亡的，但β2AR 是抗凋亡的，只有微弱的促收缩作用。G 蛋白偶联受体激酶（GRK）-2 通过磷酸化受体和诱导β-抑制蛋白（βarr）结合来使βAR 促收缩信号脱敏和拮抗。我们假设在此，GRK2 阻断可能会增强心脏中β2AR 亚型的促收缩信号。我们在体内测试了心脏靶向 GRK2 抑制对正常条件下和心力衰竭（HF）中β2AR 信号的影响。
我们将β1AR 敲除（B1KO）小鼠与心脏特异性表达βARKct 的转基因小鼠杂交，βARKct 是一种已知的 GRK2 抑制剂，并在正常条件下和心肌梗死后（MI）研究其后代。体内βARKct 的表达对于β2AR 依赖性收缩功能是必不可少的，因为异丙肾上腺素刺激β2AR 既不能增加健康或 MI 后 B1KO 小鼠的收缩力，也不能在βARKct 存在的情况下增加收缩力。其主要潜在机制是阻断磷酸二酯酶（PDE）4D 与心脏β2AR 的相互作用，这种作用通常是由 GRK2 和βarrs 对受体的作用介导的。因此，PDE4D 对β2AR 信号转导到收缩性刺激的分子“刹车”被“释放”。关于心脏β2AR 的其他有益功能，βARKct 通过减少心肌细胞凋亡和增加 MI 后早期（24 小时）与愈合相关的炎症，增加了 MI 后 B1KO 小鼠向 HF 进展的总存活率。然而，这些作用在 MI 后 4 周时消失，并且观察到心脏中另一种主要的 GRK，GRK5 的上调。
体内用βARKct 抑制 GRK2 对于心脏β2AR 的促收缩信号和功能是绝对必要的。此外，β2AR 在 MI 后 HF 中的抗凋亡信号通过βARKct 增强，尽管这种作用是短暂的。
