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-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 x 10(-4) vs. 54.1 +/- 14.8 x 10(-4), P = 0.025) and CASP model (18.3 +/- 9.4 x 10(-4) vs. 42.8 +/- 12.1 x 10(-4), 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.
Meissner
Konrad
K
Klinik für Anästhesiologie und Intensivmedizin, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald, Germany.
Kessler
Wolfram
W
Meyer zu Schwabedissen
Henriette E U
HE
Schuster
Katharina
K
Saalfeld
Kay
K
Grube
Markus
M
Buck
Anna
A
Jedlitschky
Gabriele
G
Maier
Stefan
S
Traeger
Tobias
T
Mostertz
Jörg
J
Homuth
Georg
G
Heidecke
Claus-Dieter
CD
Lehmann
Christian
C
Kroemer
Heyo K
HK
D000818:Animals; D002478:Cells, Cultured; D003106:Colon; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000097:blood / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D010538:Peritonitis / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger; D012772:Shock, Septic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D015607:Stents
D006152:Cyclic GMP; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D015850:Interleukin-6; D008070:Lipopolysaccharides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009569:Nitric Oxide; D012333:RNA, Messenger; C492376:Abcc5 protein, mouse