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

ABSTRACT: 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.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-B56? 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.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.

SUBMITTER: Golden HB

PROVIDER: S-EPMC4112368 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Golden Honey B HB Watson Linley E LE Nizamutdinov Damir D Feng Hao H Gerilechaogetu Fnu F Lal Hind H Verma Suresh K SK Mukhopadhyay Swagoto S Foster Donald M DM Dillmann Wolfgang H WH Dostal David E DE

International journal of cardiology 20130730 4

<h4>Background</h4>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.<h4>Methods and results</h4>In a time-course study of LT toxicity, echocardiography revealed acute diastolic heart failure accompanied by pulmonary regurgitation and left atrial dilation in ...[more]

PMID: 23907041

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Project description:Diastolic dysfunction is common in cardiovascular diseases, particularly in the case of heart failure with preserved ejection fraction. The challenge is to develop adequate animal models to envision human therapies in the future. It has been hypothesized that this diastolic dysfunction is linked to alterations in the nitric oxide (• NO) pathway. To investigate this issue further, we investigated the cardiac functions of a transgenic rat model (Tgβ3 ) that overexpresses the human β3 -adrenoceptor (hβ3 -AR) in the endothelium with the underlying rationale that the • NO pathway should be stimulated in the endothelium. Transgenic rats (Tgβ3 ) that express hβ3 -AR under the control of intercellular adhesion molecule 2 promoter were developed for a specific expression in endothelial cells. Transcriptomic analyses were performed on left ventricular tissue from 45-week-old rats. Among all altered genes, we focus on • NO synthase expression and endothelial function with arterial reactivity and evaluation of • NO and O2•- production. Cardiac function was characterized by echocardiography, invasive haemodynamic studies, and working heart studies. Transcriptome analyses illustrate that several key genes are regulated by the hβ3 -AR overexpression. Overexpression of hβ3 -AR leads to a reduction of Nos3 mRNA expression (-72%; P < 0.05) associated with a decrease in protein expression (-19%; P < 0.05). Concentration-dependent vasodilation to isoproterenol was significantly reduced in Tgβ3 aorta (-10%; P < 0.05), while • NO and O2•- production was increased. In the same time, Tgβ3 rats display progressively increasing diastolic dysfunction with age, as shown by an increase in the E/A filing ratio [1.15 ± 0.01 (wild type, WT) vs. 1.33 ± 0.04 (Tgβ3 ); P < 0.05] and in left ventricular end-diastolic pressure [5.57 ± 1.23 mmHg (WT) vs. 11.68 ± 1.11 mmHg (Tgβ3 ); P < 0.05]. In isolated working hearts, diastolic stress using increasing preload levels led to a 20% decrease in aortic flow [55.4 ± 1.9 mL/min (WT) vs. 45.8 ± 2.5 mL/min (Tgβ3 ); P < 0.05]. The Tgβ3 rat model displays the expected increase in • NO production upon ageing and develops diastolic dysfunction. These findings provide a further link between endothelial and cardiac dysfunction. This rat model should be valuable for future preclinical evaluation of candidate drugs aimed at correcting diastolic dysfunction.

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

Publications

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

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