Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■Wnk1的长同工型（无赖氨酸[K]激酶1）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（VSMCs）病理生理学中的作用尚不清楚。
■在Apoe-/-中注入AngII（血管紧张素II）以诱发实验性主动脉瘤。将携带Sm22-Cre等位基因的小鼠与携带FloxedWnk1等位基因的小鼠杂交，以专门研究Wnk1在VSMC中的功能作用。
■来自注入AngII的Apoe-/-小鼠的动脉瘤腹主动脉的单细胞RNA测序显示，不表达Wnk1的VSMC显示出收缩表型标志物的较低表达和增加的炎症活性。有趣的是,在人腹主动脉瘤中，VSMC中WNK1基因表达降低。Wnk1缺陷型VSMC失去其收缩功能并表现出促炎表型，以基质金属蛋白酶的产生为特征，以及细胞因子和趋化因子，这有助于炎症巨噬细胞的局部积累，Ly6Chi单核细胞，和γδT细胞。Sm22CreWnk1lox/lox小鼠在肾下腹主动脉中自发发生主动脉炎，随着时间的推移延伸到胸部区域，对长期生存没有任何负面影响。Sm22Cre+Wnk1lox/lox小鼠中的AngII输注加重了主动脉疾病,形成致命的腹主动脉瘤.使用中和抗CXCL9抗体治疗的γδT细胞募集的药理学阻断，或单核细胞/巨噬细胞使用Ki20227，CSF1受体的选择性抑制剂，减弱的主动脉炎。VSMC中Wnk1缺失导致主动脉壁重塑并破坏弹性蛋白层，胶原蛋白含量增加，并增强了局部TGF-β（转化生长因子-β）1的表达。最后,使用中和抗TGF-β抗体的体内TGF-β阻断促进Sm22CreWnk1lox/lox小鼠的囊状动脉瘤形成和主动脉破裂，但在对照动物中没有。
■Wnk1是VSMC功能的关键稳压器。Wnk1缺失促进VSMC表型向致病性促炎表型转换，在小鼠中协调有害的血管重塑和自发性严重主动脉炎。
■在Apoe-/-中注入AngII（血管紧张素II）以诱发实验性主动脉瘤。将携带Sm22-Cre等位基因的小鼠与携带FloxedWnk1等位基因的小鼠杂交，以专门研究Wnk1在VSMC中的功能作用。
■来自注入AngII的Apoe-/-小鼠的动脉瘤腹主动脉的单细胞RNA测序显示，不表达Wnk1的VSMC显示出收缩表型标志物的较低表达和增加的炎症活性。有趣的是,在人腹主动脉瘤中，VSMC中WNK1基因表达降低。Wnk1缺陷型VSMC失去其收缩功能并表现出促炎表型，以基质金属蛋白酶的产生为特征，以及细胞因子和趋化因子，这有助于炎症巨噬细胞的局部积累，Ly6Chi单核细胞，和γδT细胞。Sm22CreWnk1lox/lox小鼠在肾下腹主动脉中自发发生主动脉炎，随着时间的推移延伸到胸部区域，对长期生存没有任何负面影响。Sm22Cre+Wnk1lox/lox小鼠中的AngII输注加重了主动脉疾病,形成致命的腹主动脉瘤.使用中和抗CXCL9抗体治疗的γδT细胞募集的药理学阻断，或单核细胞/巨噬细胞使用Ki20227，CSF1受体的选择性抑制剂，减弱的主动脉炎。VSMC中Wnk1缺失导致主动脉壁重塑并破坏弹性蛋白层，胶原蛋白含量增加，并增强了局部TGF-β（转化生长因子-β）1的表达。最后,使用中和抗TGF-β抗体的体内TGF-β阻断促进Sm22CreWnk1lox/lox小鼠的囊状动脉瘤形成和主动脉破裂，但在对照动物中没有。
■Wnk1是VSMC功能的关键稳压器。Wnk1缺失促进VSMC表型向致病性促炎表型转换，在小鼠中协调有害的血管重塑和自发性严重主动脉炎。
