Hiromura Munenori, Mori Yusaku, Kohashi Kyoko, Terasaki Michishige, Shinmura Kyoko, Negoro Takaharu, Kawashima Hikaru, Kogure Mao, Wachi Toshimi, Watanabe Rena, Sato Kengo, Kushima Hideki, Tomoyasu Masako, Nakano Yasuko, Yamada Yuichiro, Watanabe Takuya, Hirano Tsutomu
Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, Showa University School of Medicine.
Circ J. 2016 Aug 25;80(9):1988-97. doi: 10.1253/circj.CJ-16-0152. Epub 2016 Jul 1.
Activation of glucose-dependent insulinotropic polypeptide receptor (GIPR) has been shown to be protective against atherosclerosis. However, effects of GIP on the heart have remained unclear. To address this question, in vitro and in vivo experiments were conducted.
In isolated mouse cardiomyocytes, GIPR mRNA was detected by reverse transcription-polymerase chain reaction, and GIP stimulation increased adenosine 3',5'-cyclic monophosphate production. In apolipoprotein E-knockout mice, infusion of angiotensin II (AngII; 2,000 ng·kg(-1)·min(-1)) significantly increased the heart weights, and co-administration of GIP (25 nmol·kg(-1)·day(-1)) reversed this increase (both P<0.01). In the left ventricular walls, GIP suppressed AngII-induced cardiomyocyte hypertrophy by 34%, apoptosis by 77%, and interstitial fibrosis by 79% (all P<0.01). Furthermore, GIP reduced AngII-induced expression of transforming growth factor-β1 (TGF-β1) and hypoxia inducible factor-1α. In wild-type mice, cardiac hypertrophy was induced by AngII to a lesser extent, and prevented by GIP. In contrast, GIP did not show any cardioprotective effect against AngII-induced cardiac hypertrophy in GIPR-knockout mice. In an in vitro experiment using mouse cardiomyocytes, GIP suppressed AngII-induced mRNA expression of B-type natriuretic peptide and TGF-β1.
It was demonstrated that cardiomyocytes represent a direct target of GIP action in vitro, and that GIP ameliorated AngII-induced cardiac hypertrophy via suppression of cardiomyocyte enlargement, apoptosis, and fibrosis in vivo. (Circ J 2016; 80: 1988-1997).
葡萄糖依赖性促胰岛素多肽受体（GIPR）的激活已被证明对动脉粥样硬化具有保护作用。然而，GIP对心脏的影响仍不清楚。为了解决这个问题，我们进行了体外和体内实验。
在分离的小鼠心肌细胞中，通过逆转录-聚合酶链反应检测到GIPR mRNA，GIP刺激增加了环磷酸腺苷的产生。在载脂蛋白E基因敲除小鼠中，输注血管紧张素II（AngII；2000 ng·kg⁻¹·min⁻¹）显著增加心脏重量，联合给予GIP（25 nmol·kg⁻¹·天⁻¹）可逆转这种增加（均P<0.01）。在左心室壁，GIP可使AngII诱导的心肌细胞肥大减少34%，细胞凋亡减少77%，间质纤维化减少79%（均P<0.01）。此外，GIP可降低AngII诱导的转化生长因子-β1（TGF-β1）和缺氧诱导因子-1α的表达。在野生型小鼠中，AngII诱导的心脏肥大程度较轻，GIP可预防这种情况。相反，在GIPR基因敲除小鼠中，GIP对AngII诱导的心脏肥大没有任何心脏保护作用。在使用小鼠心肌细胞的体外实验中，GIP可抑制AngII诱导的心钠素和TGF-β1的mRNA表达。
结果表明，心肌细胞是GIP体外作用的直接靶点，并且GIP在体内通过抑制心肌细胞肥大、凋亡和纤维化改善了AngII诱导的心脏肥大。（《循环杂志》2016年；80：1988 - 1997）
