BACKGROUND The long isoform of the Wnk1 (with-no-lysine [K] kinase 1) is a ubiquitous serine/threonine kinase, but its role in vascular smooth muscle cells (VSMCs) pathophysiology remains unknown. METHODS AngII (angiotensin II) was infused in Apoe-/- to induce experimental aortic aneurysm. Mice carrying an Sm22-Cre allele were cross-bred with mice carrying a floxed Wnk1 allele to specifically investigate the functional role of Wnk1 in VSMCs. RESULTS Single-cell RNA-sequencing of the aneurysmal abdominal aorta from AngII-infused Apoe-/- mice revealed that VSMCs that did not express Wnk1 showed lower expression of contractile phenotype markers and increased inflammatory activity. Interestingly, WNK1 gene expression in VSMCs was decreased in human abdominal aortic aneurysm. Wnk1-deficient VSMCs lost their contractile function and exhibited a proinflammatory phenotype, characterized by the production of matrix metalloproteases, as well as cytokines and chemokines, which contributed to local accumulation of inflammatory macrophages, Ly6Chi monocytes, and γδ T cells. Sm22Cre+Wnk1lox/lox mice spontaneously developed aortitis in the infrarenal abdominal aorta, which extended to the thoracic area over time without any negative effect on long-term survival. AngII infusion in Sm22Cre+Wnk1lox/lox mice aggravated the aortic disease, with the formation of lethal abdominal aortic aneurysms. Pharmacological blockade of γδ T-cell recruitment using neutralizing anti-CXCL9 (anti-CXC motif chemokine ligand 9) antibody treatment, or of monocyte/macrophage using Ki20227, a selective inhibitor of CSF1 receptor, attenuated aortitis. Wnk1 deletion in VSMCs led to aortic wall remodeling with destruction of elastin layers, increased collagen content, and enhanced local TGF-β (transforming growth factor-beta) 1 expression. Finally, in vivo TGF-β blockade using neutralizing anti-TGF-β antibody promoted saccular aneurysm formation and aorta rupture in Sm22 Cre+ Wnk1lox/lox mice but not in control animals. CONCLUSION Wnk1 is a key regulator of VSMC function. Wnk1 deletion promotes VSMC phenotype switch toward a pathogenic proinflammatory phenotype, orchestrating deleterious vascular remodeling and spontaneous severe aortitis in mice.

中文翻译：

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平滑肌细胞中 L-Wnk1 缺失会导致主动脉炎和炎症转移。


背景 Wnk1（不含赖氨酸 [K] 激酶 1）的长亚型是一种普遍存在的丝氨酸/苏氨酸激酶，但其在血管平滑肌细胞 (VSMC) 病理生理学中的作用仍不清楚。方法 将 AngII（血管紧张素 II）注入 Apoe-/- 中以诱导实验性主动脉瘤。将携带 Sm22-Cre 等位基因的小鼠与携带 floxed Wnk1 等位基因的小鼠杂交，以专门研究 Wnk1 在 VSMC 中的功能作用。结果对 AngII 输注的 Apoe-/- 小鼠的动脉瘤腹主动脉进行单细胞 RNA 测序显示，不表达 Wnk1 的 VSMC 收缩表型标记物表达较低，炎症活性增加。有趣的是，在人腹主动脉瘤中，VSMC 中的 WNK1 基因表达降低。 Wnk1缺陷的VSMC失去收缩功能并表现出促炎表型，其特征是产生基质金属蛋白酶以及细胞因子和趋化因子，这有助于炎症巨噬细胞、Ly6Chi单核细胞和γδ T细胞的局部积累。 Sm22Cre+Wnk1lox/lox 小鼠在肾下腹主动脉自发发生主动脉炎，随着时间的推移延伸至胸部区域，对长期生存没有任何负面影响。 Sm22Cre+Wnk1lox/lox 小鼠输注 AngII 会加重主动脉疾病，形成致命的腹主动脉瘤。使用中和性抗 CXCL9（抗 CXC 趋化因子配体 9）抗体治疗药物阻断 γδ T 细胞募集，或使用 Ki20227（CSF1 受体选择性抑制剂）治疗单核细胞/巨噬细胞，可减轻主动脉炎。 VSMC 中 Wnk1 缺失导致主动脉壁重塑，弹性蛋白层遭到破坏，胶原蛋白含量增加，局部 TGF-β（转化生长因子-β）1 表达增强。最后，使用中和性抗 TGF-β 抗体进行体内 TGF-β 阻断可促进 Sm22 Cre+ Wnk1lox/lox 小鼠中的囊状动脉瘤形成和主动脉破裂，但在对照动物中则不然。结论 Wnk1 是 VSMC 功能的关键调节因子。 Wnk1 缺失促进 VSMC 表型向致病性促炎表型转变，从而在小鼠中协调有害的血管重塑和自发性严重主动脉炎。