Hansen Jakob Lerche, Aplin Mark, Hansen Jonas Tind, Christensen Gitte Lund, Bonde Marie Mi, Schneider Mikael, Haunsø Stig, Schiffer Hans H, Burstein Ethan S, Weiner David M, Sheikh Søren P
Laboratory for Molecular Cardiology, The Danish National Research Foundation Centre for Cardiac Arrhythmia, The Heart Centre, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
Eur J Pharmacol. 2008 Aug 20;590(1-3):255-63. doi: 10.1016/j.ejphar.2008.05.010. Epub 2008 May 20.
The angiotensin AT(1) receptor is a key regulator of blood pressure and body fluid homeostasis, and it plays a key role in the pathophysiology of several cardiovascular diseases such as hypertension, cardiac hypertrophy, congestive heart failure, and arrhythmia. The importance of human angiotensin AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms in recombinant expression systems, primary cells and in vivo. The in vivo work clearly demonstrates profoundly different cellular consequences of angiotensin AT(1) receptor signalling in the cardiovascular system, suggesting pharmacological potential for drugs which specifically affect a subset of angiotensin AT(1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1) receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT(1) receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the human angiotensin AT(1) receptor has clear pharmacological implications for development of drugs with pathway-specific actions and defined biological outcomes.
血管紧张素AT(1)受体是血压和体液稳态的关键调节因子，在高血压、心脏肥大、充血性心力衰竭和心律失常等多种心血管疾病的病理生理学中起关键作用。血管紧张素AT(1)受体反向激动剂在临床实践中的广泛应用说明了人血管紧张素AT(1)受体信号传导的重要性。众所周知，血管紧张素AT(1)受体的啮齿动物直系同源物在重组表达系统、原代细胞和体内可通过G蛋白依赖性和非依赖性机制选择性地发出信号。体内研究清楚地表明，血管紧张素AT(1)受体信号在心血管系统中具有截然不同的细胞后果，这表明对特异性影响血管紧张素AT(1)受体部分作用的药物具有药理学潜力。然而，目前尚不清楚人血管紧张素AT(1)受体是否能通过G蛋白非依赖性机制发出信号——如果可以，这种信号传导的生理影响是什么。我们使用一系列血管紧张素类似物和针对该受体的注册药物对人血管紧张素AT(1)受体进行了详细的药理学分析。我们表明，人血管紧张素AT(1)受体直接通过G蛋白非依赖性途径发出信号，并支持NIH3T3细胞增殖。人血管紧张素AT(1)受体实现G蛋白非依赖性信号传导对开发具有途径特异性作用和明确生物学结果的药物具有明确的药理学意义。
