Department of Environmental Health and Engineering, Bloomberg School of Public Health, and.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
Am J Respir Cell Mol Biol. 2021 Aug;65(2):214-221. doi: 10.1165/rcmb.2020-0374OC.
Obesity elevates the plasma level of leptin, which has been associated with hypertension. Our recent studies in mice demonstrated that leptin increases blood pressure by activating the carotid sinus nerve, which transmits the chemosensory input from carotid bodies (CBs) to the medullary centers, and that the effect of leptin is mediated via (TRP [transient receptor potential] melastatin 7) channels in CB glomus cells. We also found that overexpression and promoter demethylation in CBs correlate positively with the hyperleptinemia and leptin receptor overexpression in CBs. Hence, we postulated that leptin epigenetically regulates expression in CBs. We addressed our hypothesis by using rat adrenal pheochromocytoma (PC12) cells as a model of CB glomus cells. PC12 cells expressing LEPRb (long, active form of leptin receptor) showed dramatic induction of the promoter activity and expression of upon leptin treatment. The increased expression coincided with the reduction of CpG site-specific methylation and trimethylation of H3K27 (H3 [histone 3] K27 [lysine 27]) and the increase of acetylation of H3K27 and trimethylation of H3K4 (H3 lysine 4) at the promoter. The inhibitor of STAT3 (signal transducer and activator of transcription 3) signaling, SD1008, reversed the leptin-induced promoter activity via modulations of the binding of pSTAT3 (phosphorylated STAT3) and DNMT3B (DNA methyltransferase 3B) and modifications of H3K27 and H3K4 at the promoter. Our results suggest that leptin-activated pSTAT3 epigenetically regulates the transcription of through DNA methylation and histone modifications. Because epigenetic changes are reversible, targeting epigenetic modifications of may serve as a new therapeutic approach for the treatment of hypertension in obesity.
肥胖会使瘦素的血浆水平升高，而瘦素与高血压有关。我们最近在小鼠身上的研究表明，瘦素通过激活颈动脉窦神经来升高血压，颈动脉窦神经将来自颈动脉体（CBs）的化学感觉输入传递到延髓中枢，而瘦素的作用是通过 CB 颗粒细胞中的 （瞬时受体电位 melastatin 7）通道介导的。我们还发现，CB 中 的过表达和启动子去甲基化与 CB 中的高瘦素血症和瘦素受体过表达呈正相关。因此，我们假设瘦素通过表观遗传调控 CB 中 的表达。我们使用大鼠肾上腺嗜铬细胞瘤（PC12）细胞作为 CB 颗粒细胞的模型来验证我们的假说。表达 LEPRb（瘦素受体的长活性形式）的 PC12 细胞在瘦素处理后，其启动子活性和 的表达显著增加。增加的 表达与 CpG 位点特异性甲基化和 H3K27（H3 [组蛋白 3] K27 [赖氨酸 27]）三甲基化的减少以及 H3K27 乙酰化和 H3K4（H3 赖氨酸 4）三甲基化的增加同时发生在 启动子上。STAT3（信号转导和转录激活因子 3）信号的抑制剂 SD1008 通过调节 pSTAT3（磷酸化 STAT3）和 DNMT3B（DNA 甲基转移酶 3B）与 启动子上的 H3K27 和 H3K4 的结合以及修饰来逆转瘦素诱导的 启动子活性。我们的结果表明，瘦素激活的 pSTAT3 通过 DNA 甲基化和组蛋白修饰来表观遗传调控 的转录。由于表观遗传变化是可逆的，靶向 的表观遗传修饰可能成为肥胖相关高血压治疗的新方法。
