Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition.
BACKGROUND
Sepsis is a systemic inflammatory response syndrome characterized by excessive production of inflammatory cytokines and cardiovascular collapse. Postreceptor signaling events that lead to stress responses and cytokine production are sensitive to redox changes and products of lipid peroxidation.


RESULTS
We tested the hypothesis that inflammatory signaling and cytokine generation during sepsis depend on the activity of the enzyme aldose reductase, which catalyzes the reduction of lipid peroxidation-derived aldehydes and their glutathione conjugates. The results of the present study show that pharmacological inhibition of aldose reductase by sorbinil or knockdown of the enzyme by small interfering RNA prevents the activation of nuclear factor-kappaB and the release of tumor necrosis factor-alpha from lipopolysaccharide-stimulated RAW264.7 or H9c2 cells. Increases in serum and cardiac cytokines in response to lipopolysaccharide challenge were suppressed by inhibition of aldose reductase. Treatment with sorbinil blunted the activation of protein kinase C, c-Jun NH2-terminal kinase, and p38, as well as phosphorylation of interleukin receptor-associated kinase, IkappaB-alpha, IkappaB kinase complex-alpha/beta, and phospholipase-gamma1 and -beta1. These changes were associated with decreased myocardial nuclear factor-kappaB and activating protein-1 activity, prostaglandin E2 production, induction of cyclooxygenase 2, and inducible nitric oxide synthase. Sorbinil treatment also induced functional recovery in myocardial fractional shortening in vivo and preserved contractile function of isolated perfused hearts. Inhibition of aldose reductase increased survival in mice injected with lethal doses of lipopolysaccharide.


CONCLUSIONS
The present demonstration that aldose reductase mediates endotoxin-induced inflammation and cardiomyopathy suggests that inhibition of this enzyme may be useful to attenuate maladaptive host responses and to treat acute cardiovascular dysfunction associated with endotoxic shock.
Ramana
Kota V
KV
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Willis
Monte S
MS
White
Michael D
MD
Horton
Jureta W
JW
DiMaio
J Michael
JM
Srivastava
Deepak
D
Bhatnagar
Aruni
A
Srivastava
Satish K
SK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006334:Heart Function Tests; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D048289:Imidazolidines / Q000494:pharmacology / Q000627:therapeutic use*; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010740:Phospholipases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D018746:Systemic Inflammatory Response Syndrome / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000447:Aldehydes; D016207:Cytokines; D020672:I-kappa B Proteins; D048289:Imidazolidines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; D000449:Aldehyde Reductase; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010740:Phospholipases; C026411:sorbinil; D005978:Glutathione; D015232:Dinoprostone