Rote of endothelin-1, sodium hydrogen exchanger-1 and mitogen activated protein kinase (MAPK) activation in glucose-induced cardiomyocyte hypertrophy
Rote of endothelin-1, sodium hydrogen exchanger-1 and mitogen activated protein kinase (MAPK) activation in glucose-induced cardiomyocyte hypertrophy
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DOI：
10.1002/dmrr.689
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发表时间：
2007-07-01
影响因子：
8
通讯作者：
Chakrabarti, Subrata
中科院分区：
文献类型：
--
作者：
Chen, Shali;Khan, Zia A.;Chakrabarti, Subrata
背景：心肌肥厚是糖尿病性心肌病的关键结构特征。先前的研究表明，糖尿病诱导的内皮素-1 （ET-1）和氢交换钠-1 （NHE-1）介导心脏的结构和功能缺陷。为了获得ET-1和NHE-1在心肌细胞肥大中作用的机制理解，我们利用体外内皮-肌细胞共培养系统来揭示可能导致糖尿病心肌细胞缺陷的细胞相互作用。方法与结果在高糖环境下培养大鼠心室心肌细胞，引起细胞肥大。高糖可上调肥厚标志物心房钠利肽（ANP）、血管紧张素原（Agt）以及诱导型一氧化氮合酶（iNOS）。用ET拮抗剂波生坦和NHE-1抑制剂cariporide处理细胞可以阻止葡萄糖诱导的心肌细胞肥大和ANP、Agt和NOS的表达。与内皮细胞共同培养的心肌细胞相比，波生坦和cariporide处理的心肌细胞产生了更明显的葡萄糖诱导的变化正常化。为了进一步探索所涉及的信号机制，我们研究了丝裂原活化蛋白激酶（MAPK）途径及其与已知在糖尿病中改变的信号蛋白的交叉相互作用。我们的研究结果表明，MAPK的激活与心肌细胞肥大有关，并被波生坦、卡利普胺和蛋白激酶C抑制。此外，MAPK的激活位于转录因子、核因子- κ B和活化蛋白-1的上游。结论ET-1和NHE-1可能通过激活MAPK介导心肌细胞肥厚，为糖尿病性心肌病的发病机制提供线索。版权所有(c) 2006约翰威利父子有限公司
Background Cardiac hypertrophy is a key structural feature of diabetic cardiomyopathy. Previous studies have shown that diabetes-induced endothelin-1 (ET-1) and sodium hydrogen exchanger-1 (NHE-1) mediate structural and functional deficits in the heart. In order to gain a mechanistic understanding of the role of ET-1 and NHE-1 in cardiomyocyte hypertrophy, we have utilized an in vitro endothelial-myocyte co-culture system to reveal cellular interactions that may arbitrate cardiomyocyte deficits in diabetes.Methods and Results Rat ventricular cardiomyocytes were cultured in high glucose levels, which caused cellular hypertrophy. Hypertrophic markers, atrial natruritic peptide (ANP) and angiotensinogen (Agt), as well as inducible nitric oxide synthase (iNOS) were upregulated by high glucose. Treatment of cells with ET antagonist bosentan and NHE-1 inhibitor cariporide prevented glucose-induced cardiomyocyte hypertrophy and expression of ANP, Agt, and NOS. Bosentan and cariporide treatment of cardiomyocytes co-cultured with endothelial cells produced a more pronounced normalization of glucose-induced changes as compared to cardiomyocyte cultured alone. To further explore the signaling mechanisms involved, we investigated the mitogen activated protein kinase (MAPK) pathway and its cross-interaction with signaling proteins known to be altered in diabetes. Our results indicate that MAPK activation is associated with cardiomyocyte hypertrophy and is inhibited by bosentan, cariporide, as well as protein kinase C inhibiton. Furthermore, MAPK activation was found to be upstream of the transcription factors, nuclear factor-kappa B and activating protein-1.Conclusion These results demonstrate that ET-1 and NHE-1 may mediate cardiomyocyte hypertrophy via MAPK activation and provide an insight into the pathogenesis of diabetic cardiomyopathy. Copyright (c) 2006 John Wiley & Sons, Ltd.