Anthrax lethal toxin induces acute diastolic dysfunction in rats through disruption of the phospholamban signaling network

作者：Golden Honey B; Watson Linley E; Nizamutdinov Damir; Feng Hao; Gerilechaogetu Fnu; Lal Hind; Verma Suresh K; Mukhopadhyay Swagoto; Foster Donald M; Dillmann Wolfgang H; Dostal David E^*

来源：International Journal of Cardiology, 2013, 168(4): 3884-3895.

DOI：10.1016/j.ijcard.2013.06.050

• Diastolic dysfunction
• Anthrax lethal toxin
• JNK1/2
• Akt
• Phospholamban

Background: Anthrax lethal toxin (LT), secreted by Bacillus anthracis, causes severe cardiac dysfunction by unknown mechanisms. LT specifically cleaves the docking domains of MAPKK (MEKs); thus, we hypothesized that LT directly impairs cardiac function through dysregulation of MAPK signaling mechanisms. %26lt;br%26gt;Methods and results: In a time-course study of LT toxicity, echocardiography revealed acute diastolic heart failure accompanied by pulmonary regurgitation and left atrial dilation in adult Sprague-Dawley rats at time points corresponding to dysregulated JNK, phospholamban (PLB) and protein phosphatase 2A (PP2A) myocardial signaling. Using isolated rat ventricular myocytes, we identified the MEK7-JNK1-PP2A-PLB signaling axis to be important for regulation of intracellular calcium (Ca-i(2+)) handling, PP2A activation and targeting of PP2A-B56 alpha to Ca-i(2+) handling proteins, such as PLB. Through a combination of gain-of-function and loss-of-function studies, we demonstrated that over-expression of MEK7 protects against LT-induced PP2A activation and Ca-i(2+) dysregulation through activation of JNK1. Moreover, targeted phosphorylation of PLB-Thr(17) by Akt improved sarcoplasmic reticulum Ca-i(2+) release and reuptake during LT toxicity. Co-immunoprecipitation experiments further revealed the pivotal role of MEK7-JNK-Akt complex formation for phosphorylation of PLB-Thr(17) during acute LT toxicity. %26lt;br%26gt;Conclusions: Our findings support a cardiogenic mechanism of LT-induced diastolic dysfunction, by which LT disrupts JNK1 signaling and results in Ca-i(2+) dysregulation through diminished phosphorylation of PLB by Akt and increased dephosphorylation of PLB by PP2A. Integration of the MEK7-JNK1 signaling module with Akt represents an important stress-activated signalosome that may confer protection to sustain cardiac contractility and maintain normal levels of Ca-i(2+) through PLB-T-17 phosphorylation. Published by Elsevier Ireland Ltd.

• 出版日期2013-10-9
• 单位西北大学