PP2A attenuates cardiac response to LPS‐induced sepsis

Abstract

Lipopolysaccharide (LPS), a cell membrane component from Gram‐negative bacteria, is involved in sepsis‐associated cardiac dysfunction. We wanted to know if protein phosphatase 2A (PP2A) influences LPS‐signaling in the heart. Therefore, we used transgenic (TG) mice with heart‐specific overexpression of PP2A. TG and littermate wild type (WT) mice were intraperitoneally injected with 30 μg LPS per g body weight or with NaCl as control (n = 14 – 18 per group). After 3 days, successful induction of LPS‐induced sepsis was monitored by enhanced plasma levels of interleukin‐6. Contractility of WT and TG hearts was analyzed using the isolated work performing heart preparation. Left ventricular systolic pressure (LVP) and the first derivative of developed pressure (+dP/dt and −dP/dt) were decreased in hearts of LPS‐treated WT mice, whereas hearts of TG mice showed no decrease of contractility after LPS‐treatment (Table). Contractile parameters Control LPS WT TG WT TG LVP (mmHg) 74±2.2 66±4.3 50±4.3* 61±1.9# +dP/dt (mmHg/s) 2481±186 2145±254 1306±246* 1901±171# −dP/dt (mmHg/s) −1371±114 −1073±139 −720±135* −1006±115 p<0.05 vs. control, p<0.05 vs. WT Quantitative PCR revealed that LPS increased IL‐6 mRNA expression in TG and WT hearts but TNFα mRNA levels only were enhanced in WT. In summary, LPS‐induced myocardial dysfunction was attenuated in TG mice compared to WT. It is tempting to speculate that increased PP2A activity in TG hearts is protective against LPS‐induced sepsis probably via diminished TNFα expression. (Supported by the DFG)