Li Xiang, Zhang Ying, Zhang Bo, Liu Xia, Hong Lan, Liu Li-Ping, Wu Cheng-Zhe, Cui Xun
Department of Physiology, School of Medical Sciences, Yanbian University, Yanji, 133-002, China.
Institute of Clinical Medicine, Yanbian University, Yanji, 133-000, China.
Prostaglandins Other Lipid Mediat. 2018 Jan;134:38-46. doi: 10.1016/j.prostaglandins.2017.12.001. Epub 2017 Dec 26.
Lipocalin-type prostaglandin D synthase (L-PGDS) and peroxisome proliferator activated receptor γ (PPARγ) play important roles in cardiovascular diseases. Nevertheless, effects of hypoxia-inducible factor 1α (HIF-1α) on L-PGDS and PPARγ protein levels and its role in hypoxia-induced atrial natriuretic peptide (ANP) secretion are unclear. In perfused beating rat atria, we observed that hypoxia significantly increased HIF-1α protein levels and stimulated ANP secretion, while upregulating L-PGDS. Hypoxia-induced ANP secretion was clearly attenuated by HIF-1α antagonist 2-methoxyestradiol, downregulating both HIF-1α and L-PGDS protein levels. It was also attenuated by L-PGDS antagonists, AT-56 and HQL-49, downregulating L-PGDS protein levels. In addition, hypoxia-induced ANP secretion was accompanied by increased PPARγ protein levels and was strongly attenuated by PPARγ antagonist GW9662. Hypoxia-induced increase in atrial PPARγ protein levels were dramatically inhibited by both 2-methoxyestradiol and AT-56. These results indicated that hypoxia promotes ANP secretion, at least in part, by activating HIF-1α-l-PGDS-PPARγ signaling in beating rat atria.
脂联素型前列腺素D合成酶（L-PGDS）和过氧化物酶体增殖物激活受体γ（PPARγ）在心血管疾病中发挥重要作用。然而，缺氧诱导因子1α（HIF-1α）对L-PGDS和PPARγ蛋白水平的影响及其在缺氧诱导的心房利钠肽（ANP）分泌中的作用尚不清楚。在灌注搏动的大鼠心房中，我们观察到缺氧显著增加HIF-1α蛋白水平并刺激ANP分泌，同时上调L-PGDS。缺氧诱导的ANP分泌被HIF-1α拮抗剂2-甲氧基雌二醇明显减弱，同时下调HIF-1α和L-PGDS蛋白水平。它也被L-PGDS拮抗剂AT-56和HQL-49减弱，下调L-PGDS蛋白水平。此外，缺氧诱导的ANP分泌伴随着PPARγ蛋白水平的增加，并被PPARγ拮抗剂GW9662强烈减弱。缺氧诱导的心房PPARγ蛋白水平增加被2-甲氧基雌二醇和AT-56显著抑制。这些结果表明，缺氧至少部分通过激活搏动大鼠心房中的HIF-1α-L-PGDS-PPARγ信号通路促进ANP分泌。
