前列环素合成酶缺乏症主要通过非 TxA2 类前列腺素/TP 轴导致内皮依赖性收缩加剧或发生,并引发心血管疾病。

IF 16.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation research Pub Date : 2024-08-30 Epub Date: 2024-07-31 DOI:10.1161/CIRCRESAHA.124.324924
Jiahui Ge, Yingbi Zhou, Hui Li, Ruhui Zeng, Kaiqi Xie, Jing Leng, Xijian Chen, Gang Yu, Xinya Shi, Yineng Xu, Dong He, Pi Guo, Yongyin Zhou, Hongjun Luo, Wenhong Luo, Bin Liu
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However, how PGIS (prostaglandin I<sub>2</sub> synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown.</p><p><strong>Methods: </strong>Experiments were performed with wild-type, <i>Pgis</i> knockout (<i>Pgis</i><sup><i>-</i>/<i>-</i></sup>) and <i>Pgis</i>/thromboxane-prostanoid receptor gene (<i>Tp</i>) double knockout (<i>Pgis</i><sup><i>-</i>/<i>-</i></sup><i>Tp</i><sup><i>-</i>/<i>-</i></sup>) mice and <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice transplanted with unfractionated wild-type or <i>Cox-1</i><sup><i>-</i>/<i>-</i></sup> bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. 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COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice though it largely suppressed the increase of plasma TxB<sub>2</sub> (TxA<sub>2</sub> metabolite) level.</p><p><strong>Conclusions: </strong>Our study demonstrates that the non-TxA<sub>2</sub> prostanoids/TP axis plays an essential role in mediating the augmentation of EDC and cardiovascular disorders when PGIS is deficient, suggesting TP as a promising therapeutic target in diseases associated with PGIS insufficiency.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e133-e149"},"PeriodicalIF":16.5000,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Prostacyclin Synthase Deficiency Leads to Exacerbation or Occurrence of Endothelium-Dependent Contraction and Causes Cardiovascular Disorders Mainly via the Non-TxA<sub>2</sub> Prostanoids/TP Axis.\",\"authors\":\"Jiahui Ge, Yingbi Zhou, Hui Li, Ruhui Zeng, Kaiqi Xie, Jing Leng, Xijian Chen, Gang Yu, Xinya Shi, Yineng Xu, Dong He, Pi Guo, Yongyin Zhou, Hongjun Luo, Wenhong Luo, Bin Liu\",\"doi\":\"10.1161/CIRCRESAHA.124.324924\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Prostaglandin I<sub>2</sub> synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. 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引用次数: 0

摘要

背景:由内皮 COX(环氧化酶)合成的前列腺素 I2 在某些血管中可引起有效的血管舒张,但在另一些血管中却会引起内皮依赖性收缩(EDC),这一点令人费解。前列腺素 I2 的产生和 EDC 在高血压等疾病中可能会增强。然而,PGIS(前列腺素 I2 合成酶)的缺乏如何影响 EDC,以及这与随之而来的心血管病变有何关联,这些问题在很大程度上仍是未知数:用野生型、Pgis 基因敲除(Pgis-/-)和 Pgis/thromboxane 类前列腺素受体基因(Tp)双敲除(Pgis-/-Tp-/-)小鼠、移植了未分化的野生型或 Cox-1-/- 骨髓细胞的 Pgis-/- 小鼠以及人类脐动脉进行了实验。通过高效液相色谱-质谱法测量了 COX 衍生的前列腺素。通过等长力测量评估了不同类型动脉的血管运动反应。监测了不同年龄小鼠的高血压、血管重塑和心脏肥大参数:结果:Pgis-/-或 PGIS 抑制的动脉在乙酰胆碱作用下产生 PGF2α、PGE2 和微量 PGD2,但不产生血栓素 A2 (TxA2)。PGIS 缺乏会导致体内外 EDC 的恶化或发生。在 Pgis-/- 主动脉中,内皮依赖性超极化没有改变,但 eNOS(内皮一氧化氮合酶)在 Ser1177 和 Thr495 的磷酸化水平发生了改变,NO 的产生和乙酰胆碱诱发的 NO 依赖性松弛明显减少。Pgis-/- 小鼠在 16 至 17 周时出现高血压和血管重塑,随后在 24 至 26 周时出现心脏肥大。与此同时,血压和心脏参数在 8 至 10 周时保持正常。额外的 TP(TxA2 受体)消融不仅抑制了 Pgis-/- 小鼠的 EDC 和 NO 信号的下调,还改善了心血管异常。在血小板存在的情况下,用乙酰胆碱刺激 Pgis-/- 血管会导致 TxA2 生成增加。骨髓衍生细胞中的 COX-1 干扰虽然在很大程度上抑制了血浆 TxB2(TxA2 代谢物)水平的升高,但未能影响 Pgis-/- 小鼠高血压的发展和血管重塑:我们的研究表明,当 PGIS 缺乏时,非 TxA2 前列腺素/TP 轴在介导 EDC 和心血管疾病的增加中发挥着重要作用,这表明 TP 是 PGIS 缺乏相关疾病的一个有前景的治疗靶点。
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Prostacyclin Synthase Deficiency Leads to Exacerbation or Occurrence of Endothelium-Dependent Contraction and Causes Cardiovascular Disorders Mainly via the Non-TxA2 Prostanoids/TP Axis.

Background: Prostaglandin I2 synthesized by endothelial COX (cyclooxygenase) evokes potent vasodilation in some blood vessels but is paradoxically responsible for endothelium-dependent constriction (EDC) in others. Prostaglandin I2 production and EDC may be enhanced in diseases such as hypertension. However, how PGIS (prostaglandin I2 synthase) deficiency affects EDC and how this is implicated in the consequent cardiovascular pathologies remain largely unknown.

Methods: Experiments were performed with wild-type, Pgis knockout (Pgis-/-) and Pgis/thromboxane-prostanoid receptor gene (Tp) double knockout (Pgis-/-Tp-/-) mice and Pgis-/- mice transplanted with unfractionated wild-type or Cox-1-/- bone marrow cells, as well as human umbilical arteries. COX-derived prostanoids were measured by high-performance liquid chromatography-mass spectrometry. Vasomotor responses of distinct types of arteries were assessed by isometric force measurement. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored.

Results: PGF, PGE2, and a trace amount of PGD2, but not thromboxane A2 (TxA2), were produced in response to acetylcholine in Pgis-/- or PGIS-inhibited arteries. PGIS deficiency resulted in exacerbation or occurrence of EDC ex vivo and in vivo. Endothelium-dependent hyperpolarization was unchanged, but phosphorylation levels of eNOS (endothelial nitric oxide synthase) at Ser1177 and Thr495 were altered and NO production and the NO-dependent relaxation evoked by acetylcholine were remarkably reduced in Pgis-/- aortas. Pgis-/- mice developed high blood pressure and vascular remodeling at 16 to 17 weeks and subsequently cardiac hypertrophy at 24 to 26 weeks. Meanwhile, blood pressure and cardiac parameters remained normal at 8 to 10 weeks. Additional ablation of TP (TxA2 receptor) not only restrained EDC and the downregulation of NO signaling in Pgis-/- mice but also ameliorated the cardiovascular abnormalities. Stimulation of Pgis-/- vessels with acetylcholine in the presence of platelets led to increased TxA2 generation. COX-1 disruption in bone marrow-derived cells failed to affect the development of high blood pressure and vascular remodeling in Pgis-/- mice though it largely suppressed the increase of plasma TxB2 (TxA2 metabolite) level.

Conclusions: Our study demonstrates that the non-TxA2 prostanoids/TP axis plays an essential role in mediating the augmentation of EDC and cardiovascular disorders when PGIS is deficient, suggesting TP as a promising therapeutic target in diseases associated with PGIS insufficiency.

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来源期刊
Circulation research
Circulation research 医学-外周血管病
CiteScore
29.60
自引率
2.00%
发文量
535
审稿时长
3-6 weeks
期刊介绍: Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.
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