Ca(2+)/Calmodulin-Dependent Protein Kinase II and Androgen Signaling Pathways Modulate MEF2 Activity in Testosterone-Induced Cardiac Myocyte Hypertrophy.
Ca(2+)/Calmodulin-Dependent Protein Kinase II and Androgen Signaling Pathways Modulate MEF2 Activity in Testosterone-Induced Cardiac Myocyte Hypertrophy.
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DOI：
10.3389/fphar.2017.00604
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发表时间：
2017
影响因子：
5.6
通讯作者：
Estrada M
中科院分区：
文献类型：
--
作者：
Duran J;Lagos D;Pavez M;Troncoso MF;Ramos S;Barrientos G;Ibarra C;Lavandero S;Estrada M
已知替吉奥通过雄激素受体（AR）依赖性和非依赖性途径诱导心肌肥大，但雄激素作用的分子基础仍知之甚少。先前的研究表明，钙/钙调素依赖性蛋白激酶II（CaMKII）和肌细胞增强因子2（MEF 2）在促进心肌细胞生长中起关键作用。为了获得雄激素对心脏的作用机制的见解，我们研究了睾酮如何影响CaMKII和MEF 2在心肌细胞肥大进行研究培养的大鼠心肌细胞和心脏从成年雄性睾丸切除（ORX）大鼠。在心肌细胞中，使用荧光素酶报告质粒监测MEF 2活性，并通过使用siRNA和靶向这两种途径的药理学抑制剂检查CaMKII和AR信号通路对MEF 2C的影响。在体内研究中，将ORX大鼠随机分配至给予载体或睾酮（125 mg/kg-1/周-1）5周的组中，并使用ELISA测定血浆睾酮浓度。通过测量充分表征的肥大标志物来评价心脏肥大。此外，蛋白质印迹法用于评估CaMKII和受磷蛋白（PLN）磷酸化，以及MEF 2C和AR蛋白水平的左心室组织提取物从对照组和睾酮治疗的ORX大鼠。而睾酮治疗增加磷酸化水平的CaMKII（Thr 286）和磷（PLN）（Thr 17）在心肌细胞中的时间和浓度依赖性的方式，睾酮诱导的MEF 2活性和心肌细胞肥大的CaMKII，MEF 2C和AR信号通路的抑制后，防止。值得注意的是，在从给予睾酮的ORX大鼠获得的肥大心脏中，CaMKII和PLN磷酸化水平以及AR和MEF 2蛋白水平均增加。因此，这项研究提出了第一个证据表明，睾酮激活MEF 2通过CaMKII和AR信号。我们的研究结果表明，一个精心策划的行动机制，涉及信号转导和转录途径的基础睾酮诱导心肌细胞肥大。
Testosterone is known to induce cardiac hypertrophy through androgen receptor (AR)-dependent and -independent pathways, but the molecular underpinnings of the androgen action remain poorly understood. Previous work has shown that Ca2+/calmodulin-dependent protein kinase II (CaMKII) and myocyte-enhancer factor 2 (MEF2) play key roles in promoting cardiac myocyte growth. In order to gain mechanistic insights into the action of androgens on the heart, we investigated how testosterone affects CaMKII and MEF2 in cardiac myocyte hypertrophy by performing studies on cultured rat cardiac myocytes and hearts obtained from adult male orchiectomized (ORX) rats. In cardiac myocytes, MEF2 activity was monitored using a luciferase reporter plasmid, and the effects of CaMKII and AR signaling pathways on MEF2C were examined by using siRNAs and pharmacological inhibitors targeting these two pathways. In the in vivo studies, ORX rats were randomly assigned to groups that were administered vehicle or testosterone (125 mg⋅kg-1⋅week-1) for 5 weeks, and plasma testosterone concentrations were determined using ELISA. Cardiac hypertrophy was evaluated by measuring well-characterized hypertrophy markers. Moreover, western blotting was used to assess CaMKII and phospholamban (PLN) phosphorylation, and MEF2C and AR protein levels in extracts of left-ventricle tissue from control and testosterone-treated ORX rats. Whereas testosterone treatment increased the phosphorylation levels of CaMKII (Thr286) and phospholambam (PLN) (Thr17) in cardiac myocytes in a time- and concentration-dependent manner, testosterone-induced MEF2 activity and cardiac myocyte hypertrophy were prevented upon inhibition of CaMKII, MEF2C, and AR signaling pathways. Notably, in the hypertrophied hearts obtained from testosterone-administered ORX rats, both CaMKII and PLN phosphorylation levels and AR and MEF2 protein levels were increased. Thus, this study presents the first evidence indicating that testosterone activates MEF2 through CaMKII and AR signaling. Our findings suggest that an orchestrated mechanism of action involving signal transduction and transcription pathways underlies testosterone-induced cardiac myocyte hypertrophy.
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影响因子：
16.6
作者：
Cannavo A;Liccardo D;Eguchi A;Elliott KJ;Traynham CJ;Ibetti J;Eguchi S;Leosco D;Ferrara N;Rengo G;Koch WJ
通讯作者：
Koch WJ
影响因子：
15.9
作者：
Backs, Johannes;Song, Kunhua;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
4.8
作者：
Di-Luoffo, Mickael;Brousseau, Catherine;Tremblay, Jacques J.
通讯作者：
Tremblay, Jacques J.
影响因子：
2.8
作者：
do Nascimento, A. M.;de Lima, E. M.;de Andrade, T. U.
通讯作者：
de Andrade, T. U.
影响因子：
39.3
作者：
English, KM;Mandour, O;Channer, KS
通讯作者：
Channer, KS