Abstract P220: Anthrax Receptor Regulation of FAK and JNK Activation in Cardiac Myocytes
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We previously demonstrated that anthrax lethal toxin (LT, protective antigen [PA] + lethal factor [LF]) produces acute systolic heart failure, characterized by increased left ventricular (LV) end-diastolic volume, reduced ejection fraction and decreased contractility in male Sprague-Dawley (SD) rats. The molecular basis for the cardiac dysfunction observed in either an animal model or clinical setting of anthrax toxicity remains to be examined. Previously, we tested LT dose-response effects on isolated neonatal rat ventricular myocytes (NRVM) at a dose of 0.05 ng/mL PA + 0.025 ng/mL LF diminished PLB and JNK phosphorylation from 1h to 4 h. During the LT+PA time-course, Akt phosphorylation at both Thr 308 and Ser 473 were also significantly reduced at all time points from 30 min to 4 h, accompanied by elevated B56 total protein and intracellular Ca 2+ , and reduced PLB phosphorylation. This response is mediated by translocation of LF into the cell through the anthrax receptors 1 and 2 (ATR1/2), which are structurally similar to integrins. In this study, we tested whether stimulation of ATR1/2 by PA alone can induce activation of the integrin effectors, FAK and JNK. Cardiac myocytes were treated time dependently (5 sec - 30 min) by PA at 0.25 ng/mL, and activation of FAK protein at different residues was determined. PA induced phosphorylation of FAK-Tyr 861 at 15 sec (p<0.05), whereas there was no effect on FAK-Tyr 397 or FAK-Tyr 925 phosphorylation for any of the time points. Furthermore, we found that PA alone maximally increased JNK phosphorylation at 15 min of treatment (p<0.05). This response was not blocked with either Losartan (10 M) or AG1479 (100 nM) indicating that neither angiotensin type I receptor (AT1) or epidermal growth factor receptor (EGFR) transactivation was involved. In summary, this study suggests a key role of ATR1/2 in mediating of signal transduction across membrane of cardiac myocytes in response to B. anthracis PA stimulation and involvement in acute responses in regulation of FAK and JNK activation in independent of AT1 and EGFR pathway.
