Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition

Kota Ramana, Monte S. Willis, Michael D. White, Jureta W. Horton, J. Michael Dimaio, Deepak Srivastava, Aruni Bhatnagar, Satish Srivastava

Research output: Contribution to journalArticle

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Abstract

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-κB and the release of tumor necrosis factor-α 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, IκB-α, IκB kinase complex-α/β, and phospholipase-γ1 and -β1. These changes were associated with decreased myocardial nuclear factor-κB 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.

Original languageEnglish (US)
Pages (from-to)1838-1846
Number of pages9
JournalCirculation
Volume114
Issue number17
DOIs
StatePublished - Oct 2006

Fingerprint

Aldehyde Reductase
Cardiomyopathies
Endotoxins
Inflammation
Cytokines
Lipopolysaccharides
Lipid Peroxidation
Sepsis
Phosphotransferases
Enzymes
Interleukin Receptors
Systemic Inflammatory Response Syndrome
Phospholipases
JNK Mitogen-Activated Protein Kinases
Nitric Oxide Synthase Type II
Cyclooxygenase 2
Septic Shock
Dinoprostone
Aldehydes
Protein Kinase C

Keywords

  • Cardiomyopathy
  • Infection
  • Inflammation
  • Inhibitors
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Ramana, K., Willis, M. S., White, M. D., Horton, J. W., Dimaio, J. M., Srivastava, D., ... Srivastava, S. (2006). Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition. Circulation, 114(17), 1838-1846. https://doi.org/10.1161/CIRCULATIONAHA.106.630830

Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition. / Ramana, Kota; Willis, Monte S.; White, Michael D.; Horton, Jureta W.; Dimaio, J. Michael; Srivastava, Deepak; Bhatnagar, Aruni; Srivastava, Satish.

In: Circulation, Vol. 114, No. 17, 10.2006, p. 1838-1846.

Research output: Contribution to journalArticle

Ramana, K, Willis, MS, White, MD, Horton, JW, Dimaio, JM, Srivastava, D, Bhatnagar, A & Srivastava, S 2006, 'Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition', Circulation, vol. 114, no. 17, pp. 1838-1846. https://doi.org/10.1161/CIRCULATIONAHA.106.630830
Ramana, Kota ; Willis, Monte S. ; White, Michael D. ; Horton, Jureta W. ; Dimaio, J. Michael ; Srivastava, Deepak ; Bhatnagar, Aruni ; Srivastava, Satish. / Endotoxin-induced cardiomyopathy and systemic inflammation in mice is prevented by aldose reductase inhibition. In: Circulation. 2006 ; Vol. 114, No. 17. pp. 1838-1846.
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AU - Willis, Monte S.

AU - White, Michael D.

AU - Horton, Jureta W.

AU - Dimaio, J. Michael

AU - Srivastava, Deepak

AU - Bhatnagar, Aruni

AU - Srivastava, Satish

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N2 - 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-κB and the release of tumor necrosis factor-α 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, IκB-α, IκB kinase complex-α/β, and phospholipase-γ1 and -β1. These changes were associated with decreased myocardial nuclear factor-κB 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.

AB - 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-κB and the release of tumor necrosis factor-α 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, IκB-α, IκB kinase complex-α/β, and phospholipase-γ1 and -β1. These changes were associated with decreased myocardial nuclear factor-κB 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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KW - Infection

KW - Inflammation

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