Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand; Molecular Medicine Graduate Program, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand; Center of Biopharmaceutical Science for Healthy Ageing (BSHA), Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand.
Eur J Pharmacol. 2022 Dec 15;937:175384. doi: 10.1016/j.ejphar.2022.175384. Epub 2022 Nov 11.
Stimulation of angiotensin II receptor (ATR) with angiotensin II (Ang II) accelerates cardiac fibroblast activation, resulting in upregulation of cytokines and growth factors. Growth factors were strongly upregulated in animal models of myocardial fibrosis and hypertrophy as well as patients with heart failure. Nevertheless, the signal transduction of ATR for upregulation of growth factors in human cardiac fibroblasts contributing to myocyte hypertrophy have not fully understood. Long-term Ang II treatment of human cardiac fibroblasts provokes the synthesis and secretion of connective tissue growth factor (CTGF), transforming growth factor beta1 (TGF-β1), and vascular endothelial growth factor (VEGF) through the ATR subtype. Blockade of G, not G or G, protein signaling inhibited ATR-mediated upregulation of CTGF, TGF-β1, and VEGF. In addition, ATR overstimulation induced upregulation of growth factors via the TGF-β-dependent and ERK1/2-dependent pathways. Growth factors secreted from cardiac fibroblasts are necessary for the induction of hypertrophic markers, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC), resulting in myocyte hypertrophy. Candesartan, irbesartan, and valsartan had greater effects than losartan for blockade of fibrotic and hypertrophic effects of Ang II. Our data support the concept whereby sustained ATR stimulation contributes to the development of myocardial fibrosis and hypertrophy, and advances understanding of this complex ATR signaling, including fibroblasts-myocytes communication during pathological conditions.
血管紧张素 II 受体 (ATR) 与血管紧张素 II (Ang II) 的刺激可加速心肌成纤维细胞的激活，导致细胞因子和生长因子的上调。在心肌纤维化和肥大的动物模型以及心力衰竭患者中，生长因子强烈上调。然而，ATR 上调生长因子的信号转导在导致心肌细胞肥大的人类心脏成纤维细胞中尚未完全理解。长期 Ang II 处理人类心脏成纤维细胞通过 ATR 亚型引发结缔组织生长因子 (CTGF)、转化生长因子 β1 (TGF-β1) 和血管内皮生长因子 (VEGF) 的合成和分泌。G 蛋白而不是 G 或 G 蛋白信号的阻断抑制了 ATR 介导的 CTGF、TGF-β1 和 VEGF 的上调。此外，ATR 过度刺激通过 TGF-β 依赖性和 ERK1/2 依赖性途径诱导生长因子的上调。心脏成纤维细胞分泌的生长因子对于诱导肥大标志物心房利钠肽 (ANP) 和β-肌球蛋白重链 (β-MHC) 是必需的，从而导致心肌细胞肥大。坎地沙坦、厄贝沙坦和缬沙坦比氯沙坦对 Ang II 的纤维化和肥大作用具有更大的阻断作用。我们的数据支持这样的概念，即持续的 ATR 刺激有助于心肌纤维化和肥大的发展，并深入了解这种复杂的 ATR 信号，包括病理条件下成纤维细胞-心肌细胞之间的通讯。
