Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Innovative Technology Research Institute of Tissue Repair and Regeneration, Key Laboratory of Regenerative Medicine, Ministry of Education, Guangzhou, Guangdong Province 510630, PR China.
Department of Plastic Surgery, Guangzhou Liuhuaqiao Hospital, Guangzhou, 510010, PR China.
Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2647-2656. doi: 10.1016/j.bbadis.2019.07.006. Epub 2019 Jul 16.
A tightly controlled activity of renin-angiotensin system (RAS) including renin, angiotensin-converting enzymes (ACEs), and angiotensin II (Ang II) receptors is critical not only for maintaining systemic hemodynamics and blood volume but also for controlling cell proliferation, differentiation, and tissue remodeling in target organs. ACE inhibitors or Ang II receptor type 1 (AT1R) blockers are widely used as first line drugs for the treatment of cardiovascular diseases that are caused by chronical activation of RAS. However, about 15% of patients using ACE inhibitors develop side effects in the skin and the underlying mechanisms have been poorly understood or even neglected. Herein we show an endogenous RAS in maintaining self-renewal and regeneration potential of epidermal stem cells (ESCs) thereby contributing to wound healing. Firstly, we found that ESCs may express ACE, and its members in wound edges were positively associated with wound healing in Captopril-treated rats. Secondly, we demonstrated that human ESCs had a functional RAS including ACE1, ACE2, Ang II, AT1R, and AT2R. ACE-Ang II axis maintains human ESC function via activation of both AT1R and AT2R, which are negatively regulated by each other. Ang II-induced activation of extracellular signal-regulated kinase (ERK) and signal transducers and activators of transcription (STAT)1 and STAT3 was mediated by the negative cross-talk between AT1R and AT2R in human ESCs. These results suggest that Ang II is a critical regulator of ESC function and ESC-mediated epidermal regeneration. Inappropriate interruption of Ang II-operated signaling may prejudice ESC function leading to impaired skin wound healing or even disease.
肾素-血管紧张素系统（RAS）的活性受到严格调控，该系统包括肾素、血管紧张素转换酶（ACE）和血管紧张素 II（Ang II）受体，它不仅对于维持全身血液动力学和血容量至关重要，而且对于控制靶器官中的细胞增殖、分化和组织重塑也至关重要。血管紧张素转换酶抑制剂或血管紧张素 II 受体 1（AT1R）阻滞剂被广泛用作治疗心血管疾病的一线药物，这些疾病是由 RAS 的慢性激活引起的。然而，大约 15%使用血管紧张素转换酶抑制剂的患者会出现皮肤副作用，但其潜在机制仍未得到很好的理解，甚至被忽视。本文中，我们展示了内源性 RAS 在维持表皮干细胞（ESCs）的自我更新和再生潜能方面的作用，从而有助于伤口愈合。首先，我们发现 ESCs 可能表达 ACE，并且其在伤口边缘的成员与卡托普利治疗大鼠的伤口愈合呈正相关。其次，我们证明了人 ESCs 具有功能性 RAS，包括 ACE1、ACE2、Ang II、AT1R 和 AT2R。ACE-Ang II 轴通过激活 AT1R 和 AT2R 来维持人 ESC 的功能，而 AT1R 和 AT2R 又相互负调控。Ang II 诱导的细胞外信号调节激酶（ERK）和信号转导和转录激活因子（STAT）1 和 STAT3 的激活是通过人 ESCs 中 AT1R 和 AT2R 之间的负交叉对话介导的。这些结果表明，Ang II 是 ESC 功能和 ESC 介导的表皮再生的关键调节剂。Ang II 操作的信号的不适当中断可能损害 ESC 功能，导致皮肤伤口愈合受损甚至疾病。
