The signal transduction cascade regulating the expression of the gap junction protein connexin43 by β-adrenoceptors
The signal transduction cascade regulating the expression of the gap junction protein connexin43 by β-adrenoceptors
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DOI：
10.1111/j.1476-5381.2009.00344.x
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发表时间：
2009-09-01
影响因子：
7.3
通讯作者：
Janousek, J.
中科院分区：
文献类型：
--
作者：
Salameh, A.;Krautblatter, S.;Janousek, J.
背景和目的：在哺乳动物心脏中，连接蛋白43 (Cx43) 代表工作心肌中的主要连接蛋白。由于β-肾上腺素受体与许多心脏疾病有关，我们希望阐明β-肾上腺素受体刺激可能控制Cx43表达的途径。实验方法：用异丙肾上腺素刺激培养的新生大鼠心肌细胞。研究了 Cx43 的表达以及 p38 丝裂原激活蛋白激酶 (MAPK)、p42/44 MAPK、JUN NH(2)-末端激酶 (JNK) 的激活以及转录因子激活蛋白 1 (AP1) 和 CRE 结合蛋白 (CREB) 的核转位。此外，我们还评估了无任何明显心脏病的患者以及充血性心力衰竭 [扩张型心肌病 (DCM)] 或肥厚型心肌病 (HCM) 患者的左心室活检中 Cx43 的表达和分布。 主要结果：异丙肾上腺素暴露导致 Cx43 蛋白上调约两倍，pEC(50) 为 7.92 +/- 0.11，这是 受普萘洛尔、SB203580 (4-(4-氟苯基)-2-(4-甲基亚磺酰基苯基)-5-(4-吡啶基)-1H-咪唑)（p38 抑制剂）、PD98059 2-(2-氨基-3-甲氧基苯基)-4H-1-苯并吡喃-4-酮) (MAPK 1) 抑制 激酶抑制剂）（Alexis Biochemicals，圣地亚哥，加利福尼亚州，美国）或环孢菌素 A。Cx43 mRNA 也获得了类似的结果。此外，Cx43 上调伴随着 p38、p42/44 和 JNK 的磷酸化，以及 AP1 和 CREB 易位至细胞核。对心室活检中 Cx43 蛋白和 mRNA 的分析显示，相对于没有任何心肌病的患者，在 DCM 患者中，Cx43 含量显着较低，而在 HCM 患者中，Cx43 含量显着较高。更重要的是，Cx43的分布也发生了变化，更多的Cx43定位于心肌细胞的侧缘。结论及意义：β-肾上腺素受体刺激通过蛋白激酶A和MAPK调节途径上调心脏Cx43的表达，可能涉及AP1和CREB。心肌病改变了 Cx43 的表达和分布。英国药理学杂志 (2009) 158, 198-208; doi:10.1111/j.1476-5381.2009.00344.x
Background and purpose: In mammalian heart, connexin43 (Cx43) represents the predominant connexin in the working myocardium. As the beta-adrenoceptor is involved in many cardiac diseases, we wanted to clarify the pathway by which beta-adrenoceptor stimulation may control Cx43 expression.Experimental approach: Cultured neonatal rat cardiomyocytes were stimulated with isoprenaline. Cx43 expression as well as activation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK, JUN NH(2)-terminalkinase (JNK) and nuclear translocation of the transcription factors activator protein 1 (AP1) and CRE-binding protein (CREB) were investigated. Additionally, we assessed Cx43 expression and distribution in left ventricular biopsies from patients without any significant heart disease, and from patients with either congestive heart failure [dilated cardiomyopathy (DCM)] or hypertrophic cardiomyopathy (HCM).Key results: Isoprenaline exposure caused about twofold up-regulation of Cx43 protein with a pEC(50) of 7.92 +/- 0.11, which was inhibited by propranolol, SB203580 (4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)-1H-imidazole) (p38 inhibitor), PD98059 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) (MAPK 1 kinase inhibitor) (Alexis Biochemicals, San Diego, CA, USA) or cyclosporin A. Similar findings were obtained for Cx43 mRNA. Furthermore, Cx43 up-regulation was accompanied by phosphorylation of p38, p42/44 and JNK, and by translocation of AP1 and CREB to the nucleus. Analysis of Cx43 protein and mRNA in ventricular biopsies revealed that in patients with DCM, Cx43 content was significantly lower, and in patients with HCM, Cx43 content was significantly higher, relative to patients without any cardiomyopathy. More importantly, Cx43 distribution also changed with more Cx43 being localized at the lateral border of the cardiomyocytes.Conclusion and implication: beta-adrenoceptor stimulation up-regulated cardiac Cx43 expression via a protein kinase A and MAPK-regulated pathway, possibly involving AP1 and CREB. Cardiomyopathy altered Cx43 expression and distribution. British Journal of Pharmacology (2009) 158, 198-208; doi:10.1111/j.1476-5381.2009.00344.x