Role of prostaglandin D2 receptors in the pathogenesis of abdominal aortic aneurysm formation.
Role of prostaglandin D2 receptors in the pathogenesis of abdominal aortic aneurysm formation.
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前列腺素D2受体在腹主动脉瘤形成中的作用
DOI：
10.1042/cs20220031
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发表时间：
2022-03-18
期刊：
影响因子：
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通讯作者：
Kim HW
中科院分区：
文献类型：
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作者：
Weintraub NL;Blomkalns AL;Ogbi M;Horimatsu T;Benson TW;Huo Y;Fulton DJ;Agarwal G;Lee R;Winkler MA;Young L;Fujise K;Guha A;Fukai T;Ushio-Fukai M;Long X;Annex BH;Kim HW
从免疫细胞或其他细胞类型释放的前列腺素D2 （PGD2）激活其受体D前列腺素受体（DP）1和2 (DP1和DP2)，促进过敏性和肺部疾病的炎症反应。前列腺素介导的炎症也可能导致血管疾病，如腹主动脉瘤（AAA）。然而，DP受体在AAA发病机制中的作用尚未得到系统的研究。在本研究中，DP1缺陷小鼠和DP1或DP2药理抑制剂在两种不同的小鼠AAA形成模型中进行了测试：血管紧张素II （AngII）输注和氯化钙（CaCl2）应用。DP1缺陷小鼠[杂合子（DP1+/−）和纯合子（DP1−/−）]可以抵抗cacl2诱导的AAA形成，同时降低基质金属肽酶（MMP）活性和外炎症细胞浸润。在AngII输注模型中，DP1+/ -小鼠，而非DP1 - / -小鼠，表现出AAA形成减少。有趣的是，在DP1−/−小鼠中，在AngII输注的反应中检测到DP2受体的代偿性上调，这表明DP2受体在AAA中可能发挥作用。使用DP1 （laropiprant）或DP2 （fevipiprant）的选择性拮抗剂治疗可以防止AAA的形成，同时减少弹性蛋白降解和主动脉炎症反应。总之，PGD2信号传导有助于小鼠AAA的形成，这表明DP受体拮抗剂可能是改善AAA的有希望的候选者，该拮抗剂已在过敏性和肺部疾病中进行了广泛的测试。
Prostaglandin D2 (PGD2) released from immune cells or other cell types activates its receptors, D prostanoid receptor (DP)1 and 2 (DP1 and DP2), to promote inflammatory responses in allergic and lung diseases. Prostaglandin-mediated inflammation may also contribute to vascular diseases such as abdominal aortic aneurysm (AAA). However, the role of DP receptors in the pathogenesis of AAA has not been systematically investigated. In the present study, DP1-deficient mice and pharmacological inhibitors of either DP1 or DP2 were tested in two distinct mouse models of AAA formation: angiotensin II (AngII) infusion and calcium chloride (CaCl2) application. DP1-deficient mice [both heterozygous (DP1+/−) and homozygous (DP1−/−)] were protected against CaCl2-induced AAA formation, in conjunction with decreased matrix metallopeptidase (MMP) activity and adventitial inflammatory cell infiltration. In the AngII infusion model, DP1+/− mice, but not DP1−/− mice, exhibited reduced AAA formation. Interestingly, compensatory up-regulation of the DP2 receptor was detected in DP1−/− mice in response to AngII infusion, suggesting a potential role for DP2 receptors in AAA. Treatment with selective antagonists of DP1 (laropiprant) or DP2 (fevipiprant) protected against AAA formation, in conjunction with reduced elastin degradation and aortic inflammatory responses. In conclusion, PGD2 signaling contributes to AAA formation in mice, suggesting that antagonists of DP receptors, which have been extensively tested in allergic and lung diseases, may be promising candidates to ameliorate AAA.