内源性 ET-1 通过激活低氧搏动大鼠心房中的 COX2-L-PGDS-PPARγ 信号促进 ANP 分泌。
Endogenous ET-1 promotes ANP secretion through activation of COX2-L-PGDS-PPARγ signaling in hypoxic beating rat atria.
机构信息
Department of Physiology, School of Medical Sciences, Yanbian University, Yanji, 133-002, China.
Institute of Clinical Medicine, Yanbian University, Yanji, 133-000, China.
出版信息
Peptides. 2019 Dec;122:170150. doi: 10.1016/j.peptides.2019.170150. Epub 2019 Sep 18.
Endothelin-1 (ET-1) is a potent stimulus for the secretion of atrial natriuretic peptide (ANP) and hypoxia stimulates the release of ET-1, which is involved in the regulation of atrial ANP secretion. However, the precise mechanism of endogenous ET-1 in the regulation of hypoxia-induced ANP secretion is unclear. Therefore, this study aimed to investigate the mechanism of hypoxia-induced endogenous ET-1 regulation of ANP secretion in isolated perfused hypoxic beating rat atria. The results of this study showed that acute hypoxia significantly stimulated ET-1 release and upregulated the expression of its type A as well as type B receptors (ETA and ETB receptors). Endogenous ET-1 induced by hypoxia markedly upregulated the expression of cyclooxygenase 2 (COX2) through activation of its two receptors, leading to an increase in lipocalin-type prostaglandin D synthase (L-PGDS) expression and prostaglandin D2 (PGD2) production. L-PGDS-derived PGD2 activated peroxisome proliferator-activated receptor γ (PPARγ), ultimately promoting hypoxia-induced ANP secretion. Conversely, L-PGDS-derived PGD2 may in turn regulate L-PGDS expression by a nuclear factor erythroid-2-related factor 2 (NRF2)-mediated feedback mechanism. These results indicate that endogenous ET-1 induced by hypoxia promotes hypoxia-induced ANP secretion by activation of COX2-L-PGDS-PPARγ signaling in beating rat atria. In addition, the positive feedback loop between L-PGDS-derived PGD2 and L-PGDS expression induced by hypoxia is part of the mechanism of hypoxia-induced ANP secretion by endogenous ET-1.
内皮素-1（ET-1）是刺激心房利钠肽（ANP）分泌的有效刺激物，而缺氧会刺激 ET-1 的释放，这与调节心房 ANP 分泌有关。然而，内源性 ET-1 调节缺氧诱导的 ANP 分泌的确切机制尚不清楚。因此，本研究旨在探讨缺氧诱导的内源性 ET-1 调节分离灌注缺氧搏动大鼠心房中 ANP 分泌的机制。本研究结果表明，急性缺氧显著刺激 ET-1 释放，并上调其 A 型和 B 型受体（ETA 和 ETB 受体）的表达。缺氧诱导的内源性 ET-1 通过激活其两个受体显着上调环氧化酶 2（COX2）的表达，导致脂钙蛋白型前列腺素 D 合酶（L-PGDS）表达和前列腺素 D2（PGD2）产生增加。L-PGDS 衍生的 PGD2 激活过氧化物酶体增殖物激活受体 γ（PPARγ），最终促进缺氧诱导的 ANP 分泌。相反，L-PGDS 衍生的 PGD2 可能通过核因子红细胞 2 相关因子 2（NRF2）介导的反馈机制反过来调节 L-PGDS 的表达。这些结果表明，缺氧诱导的内源性 ET-1 通过激活 COX2-L-PGDS-PPARγ 信号通路促进搏动大鼠心房中缺氧诱导的 ANP 分泌。此外，缺氧诱导的 L-PGDS 衍生的 PGD2 和 L-PGDS 表达之间的正反馈环是内源性 ET-1 诱导的 ANP 分泌的机制之一。
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