Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.
Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2006, Australia.
Sci Rep. 2019 Jul 29;9(1):11004. doi: 10.1038/s41598-019-47369-0.
Cardiac fibrosis is an underlying cause of diastolic dysfunction, contributing to heart failure. Substance P (SP) activation of the neurokinin-1 receptor (NK-1R) contributes to cardiac fibrosis in hypertension. However, based on in vitro experiments, this does not appear to be via direct activation of cardiac fibroblasts. While numerous cells could mediate the fibrotic effects of SP, herein, we investigate mast cells (MC) as a mechanism mediating the fibrotic actions of SP, since MCs are known to play a role in cardiac fibrosis and respond to SP. Spontaneously hypertensive rats (SHR) were treated with the NK-1R antagonist L732138 (5 mg/kg/d) from 8 to 12 weeks of age. L732138 prevented increased MC maturation of resident immature MCs. NK-1R blockade also prevented increased cardiac MC maturation in angiotensin II-infused mice. MC-deficient mice were used to test the importance of MC NK-1Rs to MC activation. MC-deficient mice administered angiotensin II did not develop fibrosis; MC-deficient mice reconstituted with MCs did develop fibrosis. MC-deficient mice reconstituted with MCs lacking the NK-1R also developed fibrosis, indicating that NK-1Rs are not required for MC activation in this setting. In conclusion, the NK-1R causes MC maturation, however, other stimuli are required to activate MCs to cause fibrosis.
心肌纤维化是舒张功能障碍的根本原因，也是心力衰竭的诱因。P 物质（SP）激活神经激肽-1 受体（NK-1R）会导致高血压中的心肌纤维化。然而，根据体外实验，这似乎不是通过对心肌成纤维细胞的直接激活。虽然许多细胞都可以介导 SP 的纤维化作用，但在此，我们研究肥大细胞（MC）作为介导 SP 纤维化作用的机制，因为已知 MC 在心肌纤维化中发挥作用，并对 SP 做出反应。自发性高血压大鼠（SHR）从 8 至 12 周龄开始接受 NK-1R 拮抗剂 L732138（5mg/kg/d）治疗。L732138 可防止内源性幼稚 MC 成熟的 MC 过度成熟。在血管紧张素 II 输注的小鼠中，NK-1R 阻断也可防止心脏 MC 成熟增加。使用 MC 缺陷型小鼠来测试 MC NK-1R 对 MC 激活的重要性。给予血管紧张素 II 的 MC 缺陷型小鼠未发生纤维化；给予 MC 的 MC 缺陷型小鼠则发生了纤维化。缺乏 NK-1R 的 MC 缺陷型小鼠也发生了纤维化，表明在这种情况下，NK-1R 不是 MC 激活所必需的。总之，NK-1R 导致 MC 成熟，但在这种情况下，还需要其他刺激来激活 MC 以引起纤维化。
