TY - JOUR
T1 - Sepsis affects cardiac expression of multidrug resistance protein 5 (MRP5, ABCC5), an ABC-type CGMP export pump
AU - Meissner, Konrad
AU - Kessler, Wolfram
AU - Meyer Zu Schwabedissen, Henriette E.U.
AU - Schuster, Katharina
AU - Saalfeld, Kay
AU - Grube, Markus
AU - Buck, Anna
AU - Jedlitschky, Gabriele
AU - Maier, Stefan
AU - Traeger, Tobias
AU - Mostertz, Jörg
AU - Homuth, Georg
AU - Heidecke, Claus Dieter
AU - Lehmann, Christian
AU - Kroemer, Heyo K.
PY - 2007/11
Y1 - 2007/11
N2 - 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-cyclic guanosine monophosphate (NO-cGMP) pathway. We have previously shown that the high-affinity cGMP export transporter, multidrug resistance protein 5 (MRP5), is expressed in the heart, which modulates intracellular concentrations and, hence, the effects of cGMP. Thus, modified expression of cardiac MRP5 in septic shock can alter cGMP concentrations and contribute to the development of heart failure. We therefore investigated MRP5 expression in the heart using two established murine models of septic shock (intraperitoneal LPS injection and surgical implantation of a stent into the ascending colon, resulting in a multibacterial peritonitis [CASP, colon ascendens stent peritonitis] in C57BL/6N mice, respectively; n = 38). Cardiac MRP5 was assessed by quantitative polymerase chain reaction and immunofluorescence. The protein was localized in the endothelial wall, smooth muscle, and cardiac myocytes. MRP5 mRNA expression was significantly reduced compared with controls both in the LPS (31.9 ± 16.8 × 10 vs. 54.1 ± 14.8 × 10, P = 0.025) and CASP model (18.3 ± 9.4 × 10 vs. 42.8 ± 12.1 × 10, P = 0.009; MRP5/glyceraldehyde 3-phosphate dehydrogenase copy numbers, respectively). In parallel, IL-6 plasma levels were significantly increased in both models. Incubation of cultured murine cardiomyocytes (HL1) 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). 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.
AB - 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-cyclic guanosine monophosphate (NO-cGMP) pathway. We have previously shown that the high-affinity cGMP export transporter, multidrug resistance protein 5 (MRP5), is expressed in the heart, which modulates intracellular concentrations and, hence, the effects of cGMP. Thus, modified expression of cardiac MRP5 in septic shock can alter cGMP concentrations and contribute to the development of heart failure. We therefore investigated MRP5 expression in the heart using two established murine models of septic shock (intraperitoneal LPS injection and surgical implantation of a stent into the ascending colon, resulting in a multibacterial peritonitis [CASP, colon ascendens stent peritonitis] in C57BL/6N mice, respectively; n = 38). Cardiac MRP5 was assessed by quantitative polymerase chain reaction and immunofluorescence. The protein was localized in the endothelial wall, smooth muscle, and cardiac myocytes. MRP5 mRNA expression was significantly reduced compared with controls both in the LPS (31.9 ± 16.8 × 10 vs. 54.1 ± 14.8 × 10, P = 0.025) and CASP model (18.3 ± 9.4 × 10 vs. 42.8 ± 12.1 × 10, P = 0.009; MRP5/glyceraldehyde 3-phosphate dehydrogenase copy numbers, respectively). In parallel, IL-6 plasma levels were significantly increased in both models. Incubation of cultured murine cardiomyocytes (HL1) 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). 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.
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U2 - 10.1097/shk.0b013e31804f5898
DO - 10.1097/shk.0b013e31804f5898
M3 - Article
C2 - 17589384
AN - SCOPUS:35649001892
SN - 1073-2322
VL - 28
SP - 564
EP - 569
JO - Shock
JF - Shock
IS - 5
ER -