Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, 832 32 Bratislava, Slovakia.
Institute of Pathophysiology, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia.
Int J Mol Sci. 2021 Nov 26;22(23):12800. doi: 10.3390/ijms222312800.
Alternative branches of the classical renin-angiotensin-aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.
经典肾素-血管紧张素-醛固酮系统（RAS）的替代分支是一个重要的级联反应，其中血管紧张素 2（AngII）通过血管紧张素转换酶 2（ACE2）的作用被切割，随后产生 Ang（1-7）和其他相关代谢物，通过 Mas 受体的激活发挥作用。通常，该 RAS 系统分支被描述为其非经典替代分支，与经典 RAS 具有平衡作用，传递血管舒张、抗炎、抗重塑和抗增殖作用。该分支的意义在许多不同的疾病中被提出，从急性心血管疾病到慢性呼吸道疾病再到癌症，但缺氧是与替代 RAS 分支活性变化相关的最突出的共同因素之一。本综述的目的是根据刺激和原因（急性与间歇性与慢性）、定位和组织（心脏与血管与肺）的不同持续时间以及所研究现象的临床相关性（实验与临床条件），深入了解各种形式的缺氧损伤对替代 RAS 分支活性的机制。此外，我们还提供了关于利用替代 RAS 作为诊断工具以及在严重与缺氧相关的心血管和心肺疾病中作为有前途的药理学靶点的未来策略的新见解。
