Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, 3200 South University Drive, Fort Lauderdale, FL, 33328, USA.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Pharmacol Rep. 2020 Feb;72(1):246-253. doi: 10.1007/s43440-019-00035-8. Epub 2020 Jan 8.
Mitogen-activated protein kinases (MAPKs) are essential molecular transducers of extracellular stimuli into intracellular responses. MAPKs are crucial in mediating actions of the renin-angiotensin-aldosterone system (RAAS), in particular, functions mediated by Angiotensin (Ang) II, the main biological peptide produced by this system. We have shown that another biologically active heptapeptide Ang III also induces MAPKs in the central nervous system. The ability of Ang III to induce MAPKs in the periphery is unknown and was the focus of this study.
We determined whether Ang III induced p38 MAPK in vascular smooth cells (VSMCs) isolated from Wistar and spontaneously hypertensive rats (SHRs) and compared these actions to those of Ang II. Further, the role of this MAPK in Ang III-mediated VSMC proliferation was also determined.
Both Ang peptides similarly induced p38 MAPK phosphorylation in VSMCs of Wistar VSMCs in a concentration- and time-dependent manner. SHR VSMCs were less sensitive to Ang III, which caused less of an effect on p38 MAPK phosphorylation in these cells. The Ang III effect was specific and occurred by activation of the Ang type 1 (AT1) receptor. The p38 MAPK pathway was also involved in Ang III-induced VSMC growth, as measured by DNA synthesis.
These findings suggest that the p38 MAPK signaling pathway is an important cascade in regulating the actions of Ang III in VSMCs. Most importantly, dysregulation of Ang III actions in these cells are apparent and may contribute to pathological conditions associated with dysfunctions in VSMCS.
丝裂原活化蛋白激酶（MAPKs）是细胞外刺激向细胞内反应转化的关键分子转导器。MAPKs 在介导肾素-血管紧张素-醛固酮系统（RAAS）的作用中至关重要，尤其是血管紧张素（Ang）II 介导的作用，Ang II 是该系统产生的主要生物肽。我们已经表明，另一种生物活性七肽 Ang III 也在中枢神经系统中诱导 MAPKs。Ang III 在周围组织中诱导 MAPKs 的能力尚不清楚，这也是本研究的重点。
我们确定 Ang III 是否在从 Wistar 和自发性高血压大鼠（SHR）分离的血管平滑肌细胞（VSMCs）中诱导 p38 MAPK，并将这些作用与 Ang II 的作用进行比较。此外，还确定了这种 MAPK 在 Ang III 介导的 VSMC 增殖中的作用。
两种肽都以浓度和时间依赖的方式在 Wistar VSMCs 中相似地诱导 p38 MAPK 磷酸化。SHR VSMCs 对 Ang III 的敏感性较低，这导致这些细胞中 p38 MAPK 磷酸化的作用较小。Ang III 的作用是特异性的，通过激活血管紧张素 1 型（AT1）受体发生。p38 MAPK 通路也参与了 Ang III 诱导的 VSMC 生长，如 DNA 合成所测量的。
这些发现表明，p38 MAPK 信号通路是调节 Ang III 在 VSMCs 中作用的重要级联反应。最重要的是，这些细胞中 Ang III 作用的失调是明显的，可能与 VSMCs 功能障碍相关的病理状况有关。
