Abstract 3604: Sepsis Affects Cardiac Expression of Multidrug Resistance Protein 5 (MRP5, ABCC5), an ABC-type cGMP Export Pump
One of the clinical characteristics associated with septic shock is heart failure. Several lines of evidence indicate that functional consequences of heart failure in septic shock are linked to the activated NO-cGMP pathway. We have previously shown that the high affinity cGMP export transporter MRP5 is expressed in heart, which modulates intracellular concentrations and hence effects of cGMP. Thus, modified expression of cardiac MRP5 in septic shock can alter cGMP concentrations and contribute to development of heart failure. We therefore investigated MRP5 expression in heart using two established murine models of septic shock (intraperitoneal lipopolysaccharide (LPS) injection and surgical implantation of a stent into the ascending colon, resulting in a multi-bacterial peritonitis (CASP) in C57BL/6N mice, respectively; n=30). Cardiac MRP5 was assessed by quantitative PCR and immunofluorescence. The protein was localized in the endothelial wall, smooth muscle and cardiac myocytes. MRP5 mRNA expression was significantly reduced compared to controls both in the LPS (31.9±16.8*10−4 vs. 54.1±14.8*10−4, P=0.025) and CASP model (18.3±9.4*10−4 vs. 42.8±12.1*10−4, P=0.009; MRP5/GAPDH copy numbers, respectively). In parallel, interleukin 6 (IL−6) plasma levels were significantly increased in both models. Incubation of cultured murine cardiomyocytes (HL−1) with 5 ng/ml IL−6 resulted in decreased expression of MRP5 (54% of control), as did incubation of the cells with serum from septic mice (LPS serum: 22% of control, CASP serum: 11% of control). Finally, a reporter gene assay using the promotor region of human MRP5 showed reduced activity following incubation with IL−6 (47% of control). In conclusion, cardiac expression of the cGMP export transporter MRP5 is decreased in two murine models of septic shock, most likely by a transcriptional mechanism. Reduced cGMP export as a consequence of decreased MRP5 expression can attenuate heart failure in sepsis.