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 Trpm7 (TRP [transient receptor potential] melastatin 7) channels in CB glomus cells. We also found that Trpm7 overexpression and Trpm7 promoter demethylation in CBs correlate positively with the hyperleptinemia and leptin receptor overexpression in CBs. Hence, we postulated that leptin epigenetically regulates Trpm7 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 Trpm7 upon leptin treatment. The increased Trpm7 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 Trpm7 promoter. The inhibitor of STAT3 (signal transducer and activator of transcription 3) signaling, SD1008, reversed the leptin-induced Trpm7 promoter activity via modulations of the binding of pSTAT3 (phosphorylated STAT3) and DNMT3B (DNA methyltransferase 3B) and modifications of H3K27 and H3K4 at the Trpm7 promoter. Our results suggest that leptin-activated pSTAT3 epigenetically regulates the transcription of Trpm7 through DNA methylation and histone modifications. Because epigenetic changes are reversible, targeting epigenetic modifications of Trpm7 may serve as a new therapeutic approach for the treatment of hypertension in obesity.

肥胖会提高瘦素的血浆水平，这与高血压有关。我们最近对小鼠的研究表明，瘦素通过激活颈动脉窦神经来增加血压，颈动脉窦神经将化学感觉输入从颈动脉体 (CBs) 传递到髓质中心，瘦素的作用是通过Trpm7 (TRP [瞬时受体电位] melastatin 7) CB 球细胞中的通道。我们还发现CBs 中的Trpm7过表达和Trpm7启动子去甲基化与 CBs 中的高瘦素血症和瘦素受体过表达正相关。因此，我们假设瘦素在表观遗传上调节Trpm7CB 中的表达。我们通过使用大鼠肾上腺嗜铬细胞瘤 (PC12) 细胞作为 CB 肾小球细胞模型来解决我们的假设。表达 LEPRb（瘦素受体的长活性形式）的 PC12 细胞在瘦素处理后显示出启动子活性和Trpm7表达的显着诱导。Trpm7表达增加与 H3K27（H3 [组蛋白 3] K27 [赖氨酸 27]）的 CpG 位点特异性甲基化和三甲基化减少以及Trpm7启动子处 H3K27 乙酰化和 H3K4（H3 赖氨酸 4）三甲基化的增加一致. STAT3（信号转导和转录激活因子 3）信号传导抑制剂 SD1008 可逆转瘦素诱导的Trpm7通过调节 pSTAT3（磷酸化 STAT3）和 DNMT3B（DNA 甲基转移酶 3B）的结合以及在Trpm7启动子处修饰 H3K27 和 H3K4 来实现启动子活性。我们的研究结果表明，瘦素激活的 pSTAT3通过 DNA 甲基化和组蛋白修饰在表观遗传上调节Trpm7的转录。由于表观遗传变化是可逆的，靶向Trpm7的表观遗传修饰可作为治疗肥胖症高血压的新治疗方法。