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
{"title":"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。","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. Prostaglandin I<sub>2</sub> production and EDC may be enhanced in diseases such as hypertension. 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. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored.</p><p><strong>Results: </strong>PGF<sub>2α</sub>, PGE<sub>2</sub>, and a trace amount of PGD<sub>2</sub>, but not thromboxane A<sub>2</sub> (TxA<sub>2</sub>), were produced in response to acetylcholine in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> 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 <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> aortas. <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> 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 (TxA<sub>2</sub> receptor) not only restrained EDC and the downregulation of NO signaling in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice but also ameliorated the cardiovascular abnormalities. Stimulation of <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> vessels with acetylcholine in the presence of platelets led to increased TxA<sub>2</sub> generation. 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. Prostaglandin I<sub>2</sub> production and EDC may be enhanced in diseases such as hypertension. 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. Parameters of hypertension, vascular remodeling, and cardiac hypertrophy in mice at different ages were monitored.</p><p><strong>Results: </strong>PGF<sub>2α</sub>, PGE<sub>2</sub>, and a trace amount of PGD<sub>2</sub>, but not thromboxane A<sub>2</sub> (TxA<sub>2</sub>), were produced in response to acetylcholine in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> 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 <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> aortas. <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> 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 (TxA<sub>2</sub> receptor) not only restrained EDC and the downregulation of NO signaling in <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> mice but also ameliorated the cardiovascular abnormalities. Stimulation of <i>Pgis</i><sup><i>-</i>/<i>-</i></sup> vessels with acetylcholine in the presence of platelets led to increased TxA<sub>2</sub> generation. 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\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Circulation research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1161/CIRCRESAHA.124.324924\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/31 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CARDIAC & CARDIOVASCULAR SYSTEMS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Circulation research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1161/CIRCRESAHA.124.324924","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/31 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
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: PGF2α, 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.
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.