Knockout of the Prostaglandin E2 Receptor Subtype 3 Promotes Eccentric Cardiac Hypertrophy and Fibrosis in Mice
Knockout of the Prostaglandin E2 Receptor Subtype 3 Promotes Eccentric Cardiac Hypertrophy and Fibrosis in Mice
复制标题
前列腺素 E2 受体亚型 3 的敲除促进小鼠心脏偏心肥大和纤维化。
DOI：
10.1177/1074248416642520
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发表时间：
2017-01-01
影响因子：
2.6
通讯作者：
Zhu, Jianhua
中科院分区：
文献类型：
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作者：
Liu, Shuang;Ji, Yawei;Zhu, Jianhua
背景：前列腺素E_2受体亚型3(EP3)是由前列腺素E_2激活的胃肠道蛋白偶联受体，在心脏保护中起着特殊的作用。本研究旨在探讨EP3缺失对心脏重构的影响，并进一步阐明可能的信号转导途径的相关参与。方法和结果：实验动物为EP3受体基因敲除(EP3KO)小鼠和16-18周龄野生型(WT)产仔对照。高分辨率超声心动图和体重指数显示EP3KO小鼠可能发生离心性心肌肥大，其心功能比WT窝小鼠差。从EP3KO心脏分离的成人心肌细胞显示自发延长。用Masson三色染色观察EP3KO小鼠的心肌纤维化。EP3KO小鼠基质基因信使RNA(MRNA)水平升高，基质金属蛋白酶2(MMP2)的mRNA、蛋白和活性水平降低，提示基质胶原合成增加，降解受到抑制。EP3KO小鼠心肌组织中细胞外信号调节激酶(ERK)1/2蛋白的磷酸化水平降低，总ERK1/2、总p38、磷酸化p38、糖原合成酶3b(GSK3b)、磷酸化GSK3b、钙调神经磷酸酶(CaN)蛋白水平及CaN活性无明显变化。结论：心脏组织中EP3基因敲除可导致16~18周龄大鼠离心性心肌肥大和心肌纤维化。EP3基因敲除的上述作用可能通过抑制MAPK/ERK通路，影响MMP2的表达而发挥作用。总体而言，PGE2-EP3是维持心脏正常生长发育所必需的。
Background: Prostaglandin E2 receptor subtype 3 (EP3), a Gi protein-coupled receptor activated by prostaglandin E2, plays a particular role in cardioprotection. This study aimed to investigate the impact of EP3 deletion on cardiac remodeling and further elucidate the related involvement of possible signaling pathways. Methods and Results: The animals used were EP3 receptor knockout (EP3KO) mice and wild-type (WT) litter mate controls at 16-18 weeks old. The high-resolution echocardiography and weight index indicated that eccentric cardiac hypertrophy might occur in EP3KO mice, which were having worse cardiac function than WT litter mates. Isolated adult myocytes from EP3KO hearts showed spontaneous lengthening. Cardiac fibrosis was observed in EP3KO mice through Masson trichrome staining. The elevated messenger RNA (mRNA) level in matrix genes and the reduced mRNA, protein, and activity levels of matrix metalloproteinase 2 (MMP-2) indicated an increased synthesis and suppressed degradation of matrix collagen in EP3KO mice. The phosphorylation level of extracellular signal-regulated kinase (ERK) 1/ 2 protein was reduced in the cardiac tissue of EP3KO mice, accompanied by no significant change in the protein level of total ERK1/2, total p38, phospho-p38, glycogen synthase kinase-3b (GSK3b), phospho-GSK3b, and calcineurin (CaN) as well as CaN activity. Conclusion: EP3 knockout in cardiac tissues could induce eccentric cardiac hypertrophy and cardiac fibrosis at 16-18 weeks old. These effects of EP3 knockout might be regulated through inactivating MAPK/ERK pathway and affecting the MMP-2 expression. Overall, PGE2-EP3 is necessary to maintain the normal growth and development of the heart.