磷酸酶独立的平滑肌钙调神经磷酸酶的活性协调导致高血压的基因表达程序。

IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences
Paula Sofía Yunes-Leites, Yilin Sun, Sara Martínez-Martínez, Álvaro Alfayate, Marta Toral, María José Méndez-Olivares, Ángel Colmenar, Ana Isabel Torralbo, Dolores López-Maderuelo, Sergio Mateos-García, David N Cornfield, Jesús Vázquez, Juan Miguel Redondo, Miguel R Campanero
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引用次数: 0

摘要

血管紧张素- ii (Ang-II)驱动高血压和腹主动脉瘤(AAA)病理性血管壁重塑的机制尚不完全清楚。以往的研究表明,钙调神经磷酸酶(Cn)的活性介导了ang - ii诱导的AAA,但Cn参与AAA形成的细胞类型尚不清楚。在这里,通过使用新创建的平滑肌细胞(SMC)特异性和内皮细胞(EC)特异性Cn缺陷小鼠(SM-Cn-/-和EC-Cn-/-小鼠),我们发现Cn在SMCs中表达,而不是EC中,是ang - ii诱导的AAA所必需的。出乎意料的是,SMC Cn在ang - ii诱导的高血压的早期发病和维持中也发挥了结构性作用,独立于其已知的磷酸酶活性。在Ang-II激活的信号通路中,Cn信号在SMCs中是必不可少的,因为主动脉中近90%的Ang-II调节基因需要在SMCs中表达Cn。Cn独立于其酶活性,精心策划了Ang-II诱导的与SMC收缩性和高血压密切相关的转录程序。SMCs中的Cn缺失,而不是其药理抑制,损害了动脉收缩性的调节。在Ang-II调控Cn表达而不需要其磷酸酶活性的基因中,我们发现Serpine1对Ang-II诱导的高血压至关重要。事实上,对PAI-1(由Serpine1编码的蛋白)的药理学抑制会损害SMCs的收缩性,并容易使高血压恢复。机制上,Serpine1的诱导是通过Cn的结构作用激活Smad2介导的。这些发现揭示了Cn在血管病理生理中的意想不到的作用,并强调PAI-1是高血压的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Phosphatase-independent activity of smooth-muscle calcineurin orchestrates a gene expression program leading to hypertension.

Angiotensin-II (Ang-II) drives pathological vascular wall remodeling in hypertension and abdominal aortic aneurysm (AAA) through mechanisms that are not completely understood. Previous studies showed that the phosphatase activity of calcineurin (Cn) mediates Ang-II-induced AAA, but the cell type involved in the action of Cn in AAA formation remained unknown. Here, by employing newly created smooth muscle cell (SMC)-specific and endothelial cell (EC)-specific Cn-deficient mice (SM-Cn-/- and EC-Cn-/- mice), we show that Cn expressed in SMCs, but not ECs, was required for Ang-II-induced AAA. Unexpectedly, SMC Cn also played a structural role in the early onset and maintenance of Ang-II-induced hypertension, independently of its known phosphatase activity. Among the signaling pathways activated by Ang-II, Cn signaling is essential in SMCs, as nearly 90% of the genes regulated by Ang-II in the aorta required Cn expression in SMCs. Cn orchestrated, independently of its enzymatic activity, the induction by Ang-II of a transcriptional program closely related to SMC contractility and hypertension. Cn deletion in SMCs, but not its pharmacological inhibition, impaired the regulation of arterial contractility. Among the genes whose regulation by Ang-II required Cn expression but not its phosphatase activity, we discovered that Serpine1 was critical for Ang-II-induced hypertension. Indeed, pharmacological inhibition of PAI-1, the protein encoded by Serpine1, impaired SMCs contractility and readily regressed hypertension. Mechanistically, Serpine1 induction was mediated by Smad2 activation via the structural role of Cn. These findings uncover an unexpected role for Cn in vascular pathophysiology and highlight PAI-1 as a potential therapeutic target for hypertension.

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来源期刊
PLoS Biology
PLoS Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOLOGY
CiteScore
15.40
自引率
2.00%
发文量
359
审稿时长
3-8 weeks
期刊介绍: PLOS Biology is the flagship journal of the Public Library of Science (PLOS) and focuses on publishing groundbreaking and relevant research in all areas of biological science. The journal features works at various scales, ranging from molecules to ecosystems, and also encourages interdisciplinary studies. PLOS Biology publishes articles that demonstrate exceptional significance, originality, and relevance, with a high standard of scientific rigor in methodology, reporting, and conclusions. The journal aims to advance science and serve the research community by transforming research communication to align with the research process. It offers evolving article types and policies that empower authors to share the complete story behind their scientific findings with a diverse global audience of researchers, educators, policymakers, patient advocacy groups, and the general public. PLOS Biology, along with other PLOS journals, is widely indexed by major services such as Crossref, Dimensions, DOAJ, Google Scholar, PubMed, PubMed Central, Scopus, and Web of Science. Additionally, PLOS Biology is indexed by various other services including AGRICOLA, Biological Abstracts, BIOSYS Previews, CABI CAB Abstracts, CABI Global Health, CAPES, CAS, CNKI, Embase, Journal Guide, MEDLINE, and Zoological Record, ensuring that the research content is easily accessible and discoverable by a wide range of audiences.
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