Upregulation of Endothelial DKK1 (Dickkopf 1) Promotes the Development of Pulmonary Hypertension Through the Sp1 (Specificity Protein 1)/SHMT2 (Serine Hydroxymethyltransferase 2) Pathway

丝氨酸羟甲基转移酶 丹麦克朗 生物 下调和上调 内分泌学 丝氨酸 细胞生物学 内科学 信号转导 生物化学 医学 Wnt信号通路 基因 磷酸化
作者
Qianqian Wang,Jingjing Tian,Xuan Li,Xiaolin Liu,Tengfei Zheng,Yachao Zhao,Xiao Li,Hongyu Zhong,Dongdong Liu,Wencheng Zhang,Meng Zhang,Mengmeng Li,Mei Zhang
出处
期刊:Hypertension [Ovid Technologies (Wolters Kluwer)]
卷期号:79 (5): 960-973 被引量:14
标识
DOI:10.1161/hypertensionaha.121.18672
摘要

Background: Pulmonary hypertension (PH) is a cancer-like proliferative disease, which has no curative treatment options. The dysfunction of pulmonary artery endothelial cells plays a key role in PH. DKK1 (Dickkopf 1) is a secretory glycoprotein that exerts proproliferative effects on tumor cells. In the present study, we aimed to identify the role and underlying mechanism of DKK1 in the development of PH, which still remain unclear. Methods and Results: We found endothelial DKK1 expression was upregulated in serum and lung tissues obtained from patients with PH, mice with hypoxia-induced PH, and human pulmonary artery endothelial cells cultured under hypoxic conditions. Endothelium-specific DKK1-knockout (DKK1 ECKO ) mice significantly ameliorated hypoxia+Sugen5416 and hypoxia-induced PH. More importantly, neutralizing anti-DKK1 antibody treatment significantly attenuated established hypoxia+Sugen5416 PH. Results of proteome analysis of control and DKK1-knockdown human pulmonary artery endothelial cells identified a significantly differentially expressed protein, SHMT2 (serine hydroxymethyltransferase 2), a key metabolic enzyme in one-carbon metabolism, as a novel DKK1 target. DKK1 knockdown in human pulmonary artery endothelial cells cultured under hypoxic conditions decreased the cellular NADPH/NADP+ ratio, increased reactive oxygen species levels and the extent of mitochondrial DNA damage, and inhibited mitochondrial membrane hyperpolarization. In the context of this altered redox defense and mitochondrial disorder, DKK1 induced a proproliferative and antiapoptotic phenotype in endothelial cells. Furthermore, we confirmed that DKK1 regulated SHMT2 transcription through the AKT–Sp1 (specificity protein 1) signaling axis. Conclusions: Our data provide robust evidence and molecular explanations for the associations between DKK1, redox defense, mitochondrial disorders, and PH and reveal a novel target for PH treatment.
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