From the Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (M.-K.S., C.G., B.H.Y.Y., L.J.K., J.S.K.S., V.Y.P.).
Unidad Médico-Quirúrgica de Enfermedades Respiratorias, Instituto de Biomedicina de Sevilla (IBiS), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Hospital Universitario Virgen del Rocío/Universidad de Sevilla, Spain (C.C.E.).
Circ Res. 2019 Nov 8;125(11):989-1002. doi: 10.1161/CIRCRESAHA.119.315338. Epub 2019 Sep 23.
Obesity leads to resistant hypertension and mechanisms are poorly understood, but high plasma levels of leptin have been implicated. Leptin increases blood pressure acting both centrally in the dorsomedial hypothalamus and peripherally. Sites of the peripheral hypertensive effect of leptin have not been identified. We previously reported that leptin enhanced activity of the carotid sinus nerve, which transmits chemosensory input from the carotid bodies (CBs) to the medullary centers, and this effect was abolished by nonselective blockers of Trp (transient receptor potential) channels. We searched our mouse CB transcriptome database and found that the Trpm7 (transient receptor potential melastatin 7) channel was the most abundant Trp channel.
To examine if leptin induces hypertension acting on the CB Trpm7.
C57BL/6J (n=79), leptin receptor () deficient mice (n=22), and LepRb-EGFP (n=4) mice were used. CB and gene expression was determined and immunohistochemistry was performed; CB glomus cells were isolated and Trpm7-like current was recorded. Blood pressure was recorded continuously in (1) leptin-treated C57BL/6J mice with intact and denervated CB; (2) leptin-treated C57BL/6J mice, which also received a nonselective Trpm7 blocker FTY720 administered systemically or topically to the CB area; (3) leptin-treated C57BL/6J mice transfected with small hairpin RNA to the CB, and (4) deficient obese mice before and after expression in CB. Leptin receptor and Trpm7 colocalized in the CB glomus cells. Leptin induced a nonselective cation current in these cells, which was inhibited by Trpm7 blockers. Leptin induced hypertension in C57BL/6J mice, which was abolished by CB denervation, Trpm 7 blockers, and small hairpin RNA applied to CBs. overexpression in CB of -deficient mice demethylated the promoter, increased gene expression, and induced hypertension.
We conclude that leptin induces hypertension acting on Trmp7 in CB, which opens horizons for new therapy.
肥胖可导致抗药性高血压，其机制尚不清楚，但已有研究表明瘦素（leptin）在血液中的水平较高。瘦素通过中枢（背内侧下丘脑）和外周途径增加血压，但其外周高血压的作用部位尚未确定。我们之前的研究表明，瘦素增强了颈动脉窦神经的活性，该神经将来自颈动脉体（carotid bodies，CBs）的化学感觉传入信号传递到延髓中枢，而这种作用可被非选择性瞬时受体电位（transient receptor potential，TRP）通道阻断剂所阻断。我们在小鼠 CB 转录组数据库中进行搜索，发现 TRPM7（transient receptor potential melastatin 7）通道是最丰富的 TRP 通道。
研究瘦素是否通过作用于 CB 的 TRPM7 而导致高血压。
使用 C57BL/6J（n=79）、瘦素受体（）缺陷型（n=22）和 LepRb-EGFP（n=4）小鼠。测定 CB 的和基因表达，并进行免疫组织化学染色；分离 CB 颗粒细胞并记录 TRPM7 样电流。连续记录以下动物的血压：（1）用瘦素处理的、完整和去神经 CB 的 C57BL/6J 小鼠；（2）用瘦素处理的、同时接受全身或局部给予 CB 区域非选择性 TRPM7 阻断剂 FTY720 的 C57BL/6J 小鼠；（3）用 CB 中的小发夹 RNA 转染的瘦素处理的 C57BL/6J 小鼠；（4）表达缺陷型肥胖（obese） 小鼠在 CB 中表达 之前和之后。瘦素受体和 TRPM7 在 CB 颗粒细胞中存在共定位。瘦素在这些细胞中诱导非选择性阳离子电流，该电流可被 TRPM7 阻断剂抑制。瘦素可诱导 C57BL/6J 小鼠高血压，该作用可被 CB 去神经、TRPM7 阻断剂和 CB 应用小发夹 RNA 所阻断。在表达缺陷型肥胖 小鼠的 CB 中过表达，可使 启动子去甲基化，增加 基因表达，并诱导高血压。
我们的结论是，瘦素通过作用于 CB 的 TRPM7 诱导高血压，这为新的治疗方法开辟了新的前景。
