Key Laboratory of Education Ministry of Xinjiang Endemic and Ethnic Diseases, NHC Key Laboratory for Prevention and Treatment of Central Asia High Incidence Diseases, Department of Pathophysiology, School of Medicine, Shihezi University, Shihezi, Xinjiang, China.
School of Medicine, Tarim University, Alaer, Xinjiang, China.
Exp Biol Med (Maywood). 2024 Apr 5;249:10112. doi: 10.3389/ebm.2024.10112. eCollection 2024.
Chronic inflammation is a key element in the progression of essential hypertension (EH). Calcium plays a key role in inflammation, so its receptor, the calcium-sensing receptor (CaSR), is an essential mediator of the inflammatory process. Compelling evidence suggests that CaSR mediates inflammation in tissues and immune cells, where it mediates their activity and chemotaxis. Macrophages (Mφs) play a major role in the inflammatory response process. This study provided convincing evidence that R568, a positive regulator of CaSR, was effective in lowering blood pressure in spontaneously hypertensive rats (SHRs), improving cardiac function by alleviating cardiac hypertrophy and fibrosis. R568 can increase the content of CaSR and M2 macrophages (M2Mφs, exert an anti-inflammatory effect) in myocardial tissue, reduce M1 macrophages (M1Mφs), which have a pro-inflammatory effect in this process. In contrast, NPS2143, a negative state regulator of CaSR, exerted the opposite effect in all of the above experiments. Following this study, R568 increased CaSR content in SHR myocardial tissue, lowered blood pressure, promoted macrophages to M2Mφs and improved myocardial fibrosis, but interestingly, both M1Mφs and M2Mφs were increased in the peritoneal cavity of SHRs, the number of M2Mφs remained lower than M1Mφs. , R568 increased CaSR content in RAW264.7 cells (a macrophage cell line), regulating intracellular Ca ([Ca]) inhibited NOD-like receptor family protein 3 (NLRP3) inflammasome activation and ultimately prevented its conversion to M1Mφs. The results showed that a decrease in CaSR in hypertensive rats causes further development of hypertension and cardiac damage. EH myocardial remodeling can be improved by CaSR overexpression by suppressing NLRP3 inflammasome activation and macrophage polarization toward M1Mφs and increasing M2Mφs.
慢性炎症是原发性高血压（EH）进展的关键因素。钙在炎症中发挥关键作用，因此其受体，钙敏感受体（CaSR），是炎症过程的重要介质。令人信服的证据表明，CaSR 介导组织和免疫细胞中的炎症，在这些组织和免疫细胞中，它介导其活性和趋化性。巨噬细胞（Mφs）在炎症反应过程中起主要作用。本研究提供了令人信服的证据，表明 CaSR 的正调节剂 R568 可有效降低自发性高血压大鼠（SHRs）的血压，通过减轻心肌肥厚和纤维化改善心脏功能。R568 可以增加心肌组织中 CaSR 和 M2 巨噬细胞（M2Mφs，发挥抗炎作用）的含量，减少 M1 巨噬细胞（M1Mφs，在这个过程中具有促炎作用）。相比之下，CaSR 的负调节状态剂 NPS2143 在所有上述实验中均产生相反的效果。在这项研究之后，R568 增加了 SHR 心肌组织中的 CaSR 含量，降低了血压，促进了巨噬细胞向 M2Mφs 的转化，并改善了心肌纤维化，但有趣的是，SHR 腹腔中 M1Mφs 和 M2Mφs 均增加，M2Mφs 的数量仍低于 M1Mφs。在 RAW264.7 细胞（巨噬细胞系）中，R568 增加了 CaSR 含量，调节细胞内 Ca[Ca]抑制 NOD 样受体家族蛋白 3（NLRP3）炎症小体的激活，最终阻止其转化为 M1Mφs。结果表明，高血压大鼠中 CaSR 的减少导致高血压和心脏损伤的进一步发展。通过抑制 NLRP3 炎症小体的激活和巨噬细胞向 M1Mφs 的极化并增加 M2Mφs 来改善 EH 心肌重构，可以通过过表达 CaSR 来实现。
