Augmented cardiac hypertrophy in response to pressure overload in mice lacking the prostaglandin I2 receptor
Augmented cardiac hypertrophy in response to pressure overload in mice lacking the prostaglandin I2 receptor
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DOI：
10.1161/circulationaha.104.527077
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发表时间：
2005-07-05
期刊：
影响因子：
37.8
通讯作者：
Ushikubi, F
中科院分区：
文献类型：
--
作者：
Hara, A;Yuhki, K;Ushikubi, F
背景 - 据报道，心脏中存在几种前列腺素类受体的表达。然而，它们在体内心脏肥大过程中的作用仍不明确。我们旨在通过使用缺乏各类受体的小鼠，来阐明这些受体在压力超负荷诱导的心脏肥大中的作用。
方法与结果 - 我们采用雌性小鼠横断主动脉缩窄术构建压力超负荷诱导的心脏肥大模型。在接受缩窄术的野生型小鼠中，在8周的观察期内出现了心脏肥大。然而，在缺乏前列腺素（PG）I - 2受体（IP - / - ）的小鼠中，在2周和4周时心脏肥大和心肌细胞肥大程度显著高于野生型小鼠，但8周时并无此差异，而缺乏IP以外其他前列腺素类受体的小鼠则未出现这种增强现象。此外，在野生型心脏中观察到的心肌纤维化在IP（ - / - ）心脏中有所加剧，且这种加剧持续长达8周。在IP（ - / - ）心脏中，作为心脏肥大代表性标志物的心房利钠肽的mRNA表达水平显著高于野生型心脏。在体外实验中，IP激动剂西卡前列素可减少血小板衍生生长因子诱导的野生型非心肌细胞增殖，尽管它无法抑制心肌营养素 - 1诱导的心肌细胞肥大。相应地，西卡前列素能有效提高非心肌细胞内的环磷腺苷（cAMP）浓度。
结论 - IP通过抑制心肌细胞肥大和心肌纤维化，在压力超负荷诱导的心脏肥大发展过程中发挥抑制作用。这两种作用被认为源于对非心肌细胞而非心肌细胞的作用。
Background - In the heart, the expressions of several types of prostanoid receptors have been reported. However, their roles in cardiac hypertrophy in vivo remain unknown. We intended to clarify the roles of these receptors in pressure overload - induced cardiac hypertrophy using mice lacking each of their receptors.Methods and Results - We used a model of pressure overload - induced cardiac hypertrophy produced by banding of the transverse aorta in female mice. In wild-type mice subjected to the banding, cardiac hypertrophy developed during the observation period of 8 weeks. In mice lacking the prostaglandin (PG) I-2 receptor (IP-/-), however, cardiac hypertrophy and cardiomyocyte hypertrophy were significantly greater than in wild-type mice at 2 and 4 weeks but not at 8 weeks, whereas there was no such augmentation in mice lacking the prostanoid receptors other than IP. In addition, cardiac fibrosis observed in wild-type hearts was augmented in IP (-/-) hearts, which persisted for up to 8 weeks. In IP (-/-) hearts, the expression level of mRNA for atrial natriuretic peptide, a representative marker of cardiac hypertrophy, was significantly higher than in wild-type hearts. In vitro, cicaprost, an IP agonist, reduced platelet-derived growth factor-induced proliferation of wild-type noncardiomyocytes, although it could not inhibit cardiotrophin-1-induced hypertrophy of cardiomyocytes. Accordingly, cicaprost increased cAMP concentration efficiently in noncardiomyocytes.Conclusions - IP plays a suppressive role in the development of pressure overload - induced cardiac hypertrophy via the inhibition of both cardiomyocyte hypertrophy and cardiac fibrosis. Both effects have been suggested as originating from the action on noncardiomyocytes rather than cardiomyocytes.