Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center (A.H.P., L.M., K.-D.M., Y.Y., J.D.C., M.A.E., E.P., H.D., E.M.-Y., B.E.I., K.W.), University of Virginia School of Medicine, Charlottesville.
Institute of Translational Pharmacology, University Hospital Düsseldorf (L.R., M.G.), Heinrich Heine University Düsseldorf, Germany.
Circ Res. 2024 Oct 11;135(9):933-950. doi: 10.1161/CIRCRESAHA.124.324492. Epub 2024 Sep 5.
Hypertension incidence increases with age and represents one of the most prevalent risk factors for cardiovascular disease. Clonal events in the hematopoietic system resulting from somatic mutations in driver genes are prevalent in elderly individuals who lack overt hematologic disorders. This condition is referred to as age-related clonal hematopoiesis (CH), and it is a newly recognized risk factor for cardiovascular disease. It is not known whether CH and hypertension in the elderly are causally related and, if so, what are the mechanistic features.
A murine model of adoptive bone marrow transplantation was employed to examine the interplay between Tet2 (ten-eleven translocation methylcytosine dioxygenase 2) clonal hematopoiesis and hypertension.
In this model, a subpressor dose of Ang II (angiotensin II) resulted in elevated systolic and diastolic blood pressure as early as 1 day after challenge. These conditions led to the expansion of Tet2-deficient proinflammatory monocytes and bone marrow progenitor populations. Tet2 deficiency promoted renal CCL5 (C-C motif ligand 5) chemokine expression and macrophage infiltration into the kidney. Consistent with macrophage involvement, Tet2 deficiency in myeloid cells promoted hypertension when mice were treated with a subpressor dose of Ang II. The hematopoietic Tet2 condition led to sodium retention, renal inflammasome activation, and elevated levels of IL (interleukin)-1β and IL-18. Analysis of the sodium transporters indicated NCC (sodium-chloride symporter) and NKCC2 (Na-K-Cl cotransporter 2) activation at residues Thr53 and Ser105, respectively. Administration of the NLRP3 (NLR family pyrin domain containing 3) inflammasome inhibitor MCC950 reversed the hypertensive state, sodium retention, and renal transporter activation.
Tet2-mediated CH sensitizes mice to a hypertensive stimulus. Mechanistically, the expansion of hematopoietic Tet2-deficient cells promotes hypertension due to elevated renal immune cell infiltration and activation of the NLRP3 inflammasome, with consequences on sodium retention. These data indicate that carriers of TET2 CH could be at elevated risk for the development of hypertension and that immune modulators could be useful in treating hypertension in this patient population.
高血压的发病率随年龄增长而增加，是心血管疾病最常见的危险因素之一。在没有明显血液系统疾病的老年人群中，由于驱动基因的体细胞突变而导致造血系统中的克隆事件很常见。这种情况被称为年龄相关性克隆性造血（CH），它是心血管疾病的一个新的危险因素。目前尚不清楚老年人群中的 CH 和高血压是否存在因果关系，如果存在，其机制特征是什么。
采用过继性骨髓移植的小鼠模型来研究 Tet2（十号染色体缺失的磷酸酶张力蛋白同源物 2）克隆性造血与高血压之间的相互作用。
在该模型中，亚加压剂量的 Ang II（血管紧张素 II）在挑战后 1 天即可导致收缩压和舒张压升高。这些情况导致 Tet2 缺陷的促炎单核细胞和骨髓祖细胞群体扩增。Tet2 缺陷促进肾脏 CCL5（C 型趋化因子配体 5）趋化因子表达和巨噬细胞浸润肾脏。与巨噬细胞参与一致，当用亚加压剂量的 Ang II 处理时，髓系细胞中的 Tet2 缺陷促进了高血压。造血 Tet2 状态导致钠潴留、肾炎症小体激活和白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）水平升高。对钠转运体的分析表明，NCC（钠-氯共转运体）和 NKCC2（Na-K-Cl 共转运体 2）分别在残基 Thr53 和 Ser105 处被激活。NLRP3（NLR 家族含有pyrin 结构域的 3）炎症小体抑制剂 MCC950 的给药逆转了高血压状态、钠潴留和肾脏转运体的激活。
Tet2 介导的 CH 使小鼠对高血压刺激敏感。从机制上讲，造血 Tet2 缺陷细胞的扩增通过增加肾脏免疫细胞浸润和 NLRP3 炎症小体的激活促进高血压，导致钠潴留。这些数据表明，携带 TET2 CH 的患者发生高血压的风险可能增加，免疫调节剂可能对该患者群体的高血压治疗有用。
