Perrino Cinzia, Rockman Howard A, Chiariello Massimo
Division of Cardiology, University Federico II, Via Pansini 5, Naples, 80131, Italy.
Vascul Pharmacol. 2006 Aug;45(2):77-85. doi: 10.1016/j.vph.2006.01.018. Epub 2006 Jun 27.
Human heart failure is a complex clinical syndrome characterized by extensive abnormalities in the beta-adrenergic receptor (betaAR) system. Normalization of betaAR signalling consistently ameliorates cardiac dysfunction and survival in heart failure, suggesting that betaAR dysfunction may be intrinsically linked to the deterioration of cardiac performance. Agonist-dependent phosphorylation of betaARs by betaAR kinase 1 (betaARK1) initiates the processes of desensitization and downregulation, hallmarks of heart failure. Our recent studies have shown that betaARK1 forms a cytosolic complex with phosphoinositide 3-kinase (PI3K) and that translocation of betaARK1 to the plasma membrane also promotes the betaAR-targeting of PI3Ks. At the plasma membrane, the generation of 3'-phosphorylated phosphatidylinositols by PI3K is required in the process of endocytosis, a prodrome to receptor downregulation. A large body of data now indicates that betaAR-targeting of PI3Ks is consistently associated with abnormalities of betaAR signalling under pathological conditions, including pressure-overload hypertrophy and heart failure from different causes. In this review we will discuss the role of betaAR-targeted PI3K activity and novel experimental strategies to disrupt the betaARK1/PI3K complex and in turn ameliorate betaAR dysfunction and the progression of heart failure.
人类心力衰竭是一种复杂的临床综合征，其特征是β-肾上腺素能受体（βAR）系统存在广泛异常。βAR信号转导正常化可持续改善心力衰竭患者的心脏功能障碍并提高生存率，这表明βAR功能障碍可能与心脏功能恶化存在内在联系。βAR激酶1（βARK1）介导的βAR激动剂依赖性磷酸化启动了脱敏和下调过程，这是心力衰竭的标志。我们最近的研究表明，βARK1与磷酸肌醇3激酶（PI3K）形成胞质复合物，并且βARK1向质膜的转位也促进了PI3K对βAR的靶向作用。在质膜上，PI3K生成3'-磷酸化磷脂酰肌醇是内吞作用过程所必需的，内吞作用是受体下调的前驱。大量数据表明，在病理条件下，包括压力超负荷肥大和不同原因导致的心力衰竭，PI3K对βAR的靶向作用始终与βAR信号转导异常相关。在这篇综述中，我们将讨论PI3K靶向βAR的活性作用以及破坏βARK1/PI3K复合物进而改善βAR功能障碍和心力衰竭进展的新实验策略。
