Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts.
Notch1 Mediates Preconditioning Protection Induced by GPER in Normotensive and Hypertensive Female Rat Hearts.
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DOI：
10.3389/fphys.2018.00521
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发表时间：
2018
影响因子：
4
通讯作者：
Penna C
中科院分区：
文献类型：
--
作者：
Rocca C;Femminò S;Aquila G;Granieri MC;De Francesco EM;Pasqua T;Rigiracciolo DC;Fortini F;Cerra MC;Maggiolini M;Pagliaro P;Rizzo P;Angelone T;Penna C
G蛋白偶联雌激素受体(GPER)是一种表达于心血管系统的雌激素受体。G1是一种选择性GPER配体，通过激活PI3K-Akt通路和Notch信号在正常血压动物中发挥心血管作用。在这里，我们研究了G1/GPER相互作用是否参与了限制雌性自发性高血压大鼠(SHR)心肌梗死面积和改善缺血后收缩功能。在该模型中，我们还研究了Notch信号和生存途径的关键组成部分，即PI3K-Akt、一氧化氮合酶(NOS)和线粒体K+-ATP(MitoKATP)通道。从雌性SHR分离的大鼠心脏进行30min的常温全脑缺血和120min的再灌流。G1期(10 NM)单独灌流或GPER、PI3K/NOS和MitoKATP通道的特异性阻断剂与G1期共同灌流。用Western blotting研究Notch1的参与情况。测量心肌梗死面积和左心室内压。为证实Notch信号对H9c2细胞的非内皮依赖性保护作用，用该信号的特异性抑制剂N-[N-(3，5-二氟苯乙酰)-L-丙氨基]-S-苯甘氨酸叔丁酯(5μM)对H9c2细胞进行了研究。利用DAPT，我们证实了G1/Notch信号参与了限制正常血压动物心脏梗死范围。在高血压模型中，GPER、PI3K/NOS和MitoKATP通道的抑制可阻止G1诱导的心肌梗死面积的缩小和心功能的改善。在高血压模型和正常血压模型和心肌细胞系中，通过免疫印迹证实了Notch的参与，并通过特异性抑制物证实了Notch的参与。我们的结果表明，在正常血压和高血压条件下，GPERs在介导预适应心脏保护中起着关键作用。G1诱导的保护涉及Notch1，并能够在存在共病的情况下激活生存通路。包括高血压在内的几种病理情况会降低缺血调节策略的效果。然而，G1诱导的保护可以显著减少高血压动物的I/R损伤。进一步的研究可能会确定这一结果的临床翻译。
G protein-coupled estrogen receptor (GPER) is an estrogen receptor expressed in the cardiovascular system. G1, a selective GPER ligand, exerts cardiovascular effects through activation of the PI3K-Akt pathway and Notch signaling in normotensive animals. Here, we investigated whether the G1/GPER interaction is involved in the limitation of infarct size, and improvement of post-ischemic contractile function in female spontaneous hypertensive rat (SHR) hearts. In this model, we also studied Notch signaling and key components of survival pathway, namely PI3K-Akt, nitric oxide synthase (NOS) and mitochondrial K+-ATP (MitoKATP) channels. Rat hearts isolated from female SHR underwent 30 min of global, normothermic ischemia and 120 min of reperfusion. G1 (10 nM) alone or specific inhibitors of GPER, PI3K/NOS and MitoKATP channels co-infused with G1, just before I/R, were studied. The involvement of Notch1 was studied by Western blotting. Infarct size and left ventricular pressure were measured. To confirm endothelial-independent G1-induced protection by Notch signaling, H9c2 cells were studied with specific inhibitor, N-[N-(3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT, 5 μM), of this signaling. Using DAPT, we confirmed the involvement of G1/Notch signaling in limiting infarct size in heart of normotensive animals. In the hypertensive model, G1-induced reduction in infarct size and improvement of cardiac function were prevented by the inhibition of GPER, PI3K/NOS, and MitoKATP channels. The involvement of Notch was confirmed by western blot in the hypertensive model and by the specific inhibitor in the normotensive model and cardiac cell line. Our results suggest that GPERs play a pivotal role in mediating preconditioning cardioprotection in normotensive and hypertensive conditions. The G1-induced protection involves Notch1 and is able to activate the survival pathway in the presence of comorbidity. Several pathological conditions, including hypertension, reduce the efficacy of ischemic conditioning strategies. However, G1-induced protection can result in significant reduction of I/R injury also female in hypertensive animals. Further studies may ascertain the clinical translation of the present results.
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影响因子：
5
作者：
Menazza S;Sun J;Appachi S;Chambliss KL;Kim SH;Aponte A;Khan S;Katzenellenbogen JA;Katzenellenbogen BS;Shaul PW;Murphy E
通讯作者：
Murphy E
影响因子：
9.3
作者：
Deschamps, Anne M.;Murphy, Elizabeth;Sun, Junhui
通讯作者：
Sun, Junhui
Stilbenoids重塑乳腺癌细胞中的DNA甲基化模式，并通过MAML2转录活性的表观遗传调节来抑制致癌缺口信号传导。
影响因子：
4.7
作者：
Lubecka K;Kurzava L;Flower K;Buvala H;Zhang H;Teegarden D;Camarillo I;Suderman M;Kuang S;Andrisani O;Flanagan JM;Stefanska B
通讯作者：
Stefanska B
影响因子：
7.3
作者：
Feng Y;Madungwe NB;da Cruz Junho CV;Bopassa JC
通讯作者：
Bopassa JC
DOI：
10.1111/j.1530-0277.2009.00939.x
发表时间：
2009-07
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
El-Mas MM;Fan M;Abdel-Rahman AA
通讯作者：
Abdel-Rahman AA