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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.
Ge, Jiahui; Zhou, Yingbi; Li, Hui; Zeng, Ruhui; Xie, Kaiqi; Leng, Jing; Chen, Xijian; Yu, Gang; Shi, Xinya; Xu, Yineng; He, Dong; Guo, Pi; Zhou, Yongyin; Luo, Hongjun; Luo, Wenhong; Liu, Bin.
Afiliación
  • Ge J; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
  • Zhou Y; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
  • Li H; Bio-Analytical Laboratory (H. Li, Yongyin Zhou, H. Luo, W.L.), Shantou University Medical College, China.
  • Zeng R; Department of Gynaecology and Obstetrics, First Affiliated Hospital, Shantou University Medical College, China (R.Z.).
  • Xie K; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
  • Leng J; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
  • Chen X; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
  • Yu G; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
  • Shi X; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
  • Xu Y; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
  • He D; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
  • Guo P; Department of Preventive Medicine (P.G.), Shantou University Medical College, China.
  • Zhou Y; Bio-Analytical Laboratory (H. Li, Yongyin Zhou, H. Luo, W.L.), Shantou University Medical College, China.
  • Luo H; Bio-Analytical Laboratory (H. Li, Yongyin Zhou, H. Luo, W.L.), Shantou University Medical College, China.
  • Luo W; Bio-Analytical Laboratory (H. Li, Yongyin Zhou, H. Luo, W.L.), Shantou University Medical College, China.
  • Liu B; Cardiovascular Research Center (J.G., Yingbi Zhou, K.X., J.L., X.C., G.Y., X.S., Y.X., D.H., B.L.), Shantou University Medical College, China.
Circ Res ; 135(6): e133-e149, 2024 Aug 30.
Article en En | MEDLINE | ID: mdl-39082135
ABSTRACT

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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vasoconstricción / Endotelio Vascular / Prostaglandinas / Ratones Noqueados / Oxidorreductasas Intramoleculares / Ratones Endogámicos C57BL Límite: Animals / Humans / Male Idioma: En Revista: Circ Res Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Vasoconstricción / Endotelio Vascular / Prostaglandinas / Ratones Noqueados / Oxidorreductasas Intramoleculares / Ratones Endogámicos C57BL Límite: Animals / Humans / Male Idioma: En Revista: Circ Res Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos