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

Abstract

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.

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(2+)(i)) handling, PP2A activation and targeting of PP2A-B56α to Ca(2+)(i) 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(2+)(i) dysregulation through activation of JNK1. Moreover, targeted phosphorylation of PLB-Thr(17) by Akt improved sarcoplasmic reticulum Ca(2+)(i) 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.

CONCLUSIONS:

Our findings support a cardiogenic mechanism of LT-induced diastolic dysfunction, by which LT disrupts JNK1 signaling and results in Ca(2+)(i) 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(2+)(i) through PLB-T(17) phosphorylation.

• Authors: Honey B Golden, Linley E Watson, Damir Nizamutdinov, Hao Feng, Fnu Gerilechaogetu, Hind Lal, Suresh K Verma, Swagoto Mukhopadhyay, Donald M Foster, Wolfgang H Dillmann, David E Dostal
• Journal: International journal of cardiology (Int J Cardiol) Vol. 168 Issue 4 Pg. 3884-95 (Oct 09 2013) ISSN: 1874-1754 [Electronic] Netherlands
• PMID: 23907041 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2013.

Chemical References

• Antigens, Bacterial
• Bacterial Toxins
• Calcium-Binding Proteins
• anthrax toxin
• phospholamban

Topics

• Acute Disease
• Animals
• Antigens, Bacterial (toxicity)
• Bacterial Toxins (toxicity)
• Calcium-Binding Proteins (antagonists & inhibitors, metabolism)
• Cells, Cultured
• Heart Failure, Diastolic (chemically induced, metabolism)
• Male
• Myocytes, Cardiac (drug effects, metabolism)
• Phosphorylation (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)