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(Circulation. 2006;114:1838-1846.)
© 2006 American Heart Association, Inc.

Heart Failure

Endotoxin-Induced Cardiomyopathy and Systemic Inflammation in Mice Is Prevented by Aldose Reductase Inhibition

Kota V. Ramana, PhD; Monte S. Willis, MD, PhD; Michael D. White, BS; Jureta W. Horton, PhD; J. Michael DiMaio, MD; Deepak Srivastava, MD; Aruni Bhatnagar, PhD; Satish K. Srivastava, PhD

From the Department of Biochemistry and Molecular Biology (K.V.R., S.K.S.), University of Texas Medical Branch, Galveston, Tex; Departments of Surgery (M.S.W., M.D.W., J.W.H., J.M.D.) and Pathology (M.S.W.), University of Texas Southwestern Medical Center, Dallas, Tex; Gladstone Institute of Cardiovascular Disease and Department of Pediatrics (D.S.), University of California, San Francisco; and Institute of Molecular Cardiology (A.B.), University of Louisville, Louisville, Ky.

Correspondence to Satish K. Srivastava, Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555. E-mail ssrivast{at}utmb.edu

Received March 30, 2006; revision received August 23, 2006; accepted August 25, 2006.

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.

Methods and 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-B and the release of tumor necrosis factor- 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, IB-, IB kinase complex-/ß, and phospholipase-1 and -ß1. These changes were associated with decreased myocardial nuclear factor-B 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.

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