Key roles of endothelin-1 and p38 MAPK in the regulation of atrial stretch response
Key roles of endothelin-1 and p38 MAPK in the regulation of atrial stretch response
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DOI：
10.1152/ajpregu.00853.2009
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发表时间：
2011-01-01
影响因子：
2.8
通讯作者：
Ruskoaho, Heikki
中科院分区：
文献类型：
--
作者：
Kerkela, Risto;Ilves, Mika;Ruskoaho, Heikki
[10]杨文辉，李文辉.内皮素-1和p38 MAPK在心房牵张反应调节中的关键作用Am J Physiol Regul Integr Comp Physiol 300：R140-R149，2011.首次发表于2010年11月17日; doi：10.1152/ajpregu.00853.2009.-左心室牵张反应的调节机制已被详细研究，但在心房心肌中还不清楚。心房肌的肥大生长是心房颤动的发病机制之一。在这项研究中，我们试图阐明牵张诱导激活的关键信号通路和肥大相关基因在大鼠心房的机制。牵拉离体心房可诱导p38 MAPK和ERK磷酸化的快速增加，并诱导转录因子Elk-1和加塔-4的DNA结合活性的p38 MAPK依赖性增加。ERK通路的抑制对所研究的心脏转录因子没有影响。牵拉诱导的心房收缩功能的增加通过抑制p38 MAPK而显著增强。p38 MAPK还调节牵张诱导的c-fos、β-肌球蛋白重链、B型利钠肽mRNA水平和心房利钠肽分泌的增加。已知各种自分泌/旁分泌因子介导左心室的牵张反应。牵拉离体心房导致内皮素-1（ET-1）mRNA水平显著增加，而爱帕琳和肾上腺髓质素信号级联下调。给予混合ET（A/B）受体拮抗剂波生坦可减弱牵张诱导的离体心房加塔-4激活，而ANG II 1型受体拮抗剂CV-11974则无此作用。此外，分析RNA从完整的心房和心室肌显示显着较高的ETA受体和ET转换酶-1的mRNA水平在心房相比，心室肌。总之，我们的研究结果确定了当地的ET-1系统和p38 MAPK的关键调节负荷诱导的肥大反应在离体大鼠心房。
Kerkela R, Ilves M, Pikkarainen S, Tokola H, Ronkainen V-P, Majalahti T, Leppaluoto J, Vuolteenaho O, Ruskoaho H. Key roles of endothelin-1 and p38 MAPK in the regulation of atrial stretch response. Am J Physiol Regul Integr Comp Physiol 300: R140-R149, 2011. First published November 17, 2010; doi:10.1152/ajpregu.00853.2009.-Mechanisms regulating stretch response in the left ventricle are investigated in detail but not well understood in atrial myocardium. Hypertrophic growth of atrial myocardium contributes to the pathogenesis of atrial fibrillation. In this study, we sought to elucidate mechanisms of stretch-induced activation of key signaling pathways and hypertrophy-associated genes in rat atria. Stretching of isolated atria induced a rapid increase in phosphorylation of p38 MAPK and ERK and induced a p38 MAPK-dependent increase in DNA binding activity of transcription factors Elk-1 and GATA-4. Inhibition of the ERK pathway had no effect on the cardiac transcription factors studied. Stretch-induced increase in atrial contractile function was substantially enhanced by inhibition of p38 MAPK. p38 MAPK also regulated stretch-induced increase in c-fos, beta-myosin heavy chain, B-type natriuretic peptide mRNA levels, and atrial natriuretic peptide secretion in isolated atria. Various autocrine/paracrine factors are known to mediate the stretch response in the left ventricle. Stretching of isolated atria resulted in a robust increase in endothelin-1 (ET-1) mRNA levels, while apelin and adrenomedullin signaling cascades were downregulated. Administration of mixed ET(A/B) receptor antagonist bosentan attenuated the stretch-induced activation of GATA-4 in isolated atria, whereas ANG II receptor type-1 antagonist CV-11974 had no effect. Moreover, analysis of RNA from intact atrial and ventricular myocardium revealed significantly higher mRNA levels of ETA receptor and ET converting enzyme-1 in atrial compared with ventricular myocardium. In conclusion, our findings identify the local ET-1 system and p38 MAPK as key regulators of load-induced hypertrophic response in isolated rat atria.