Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy

Masaaki Ii, Hiromi Nishimura, Kengo F. Kusano, Gangjian Qin, Youngsup Yoon, Andrea Wecker, Takayuki Asahara, Douglas W. Losordo

Research output: Contribution to journalArticle

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Abstract

Background - Peripheral neuropathy is a frequent and major complication of diabetes. Methods and Results - Severe peripheral neuropathy developed in type II diabetic mice, characterized by significant slowing of motor and sensory nerve conduction velocities. Rosuvastatin restored nerve vascularity, including vessel size, and nerve function also recovered to the levels of nondiabetic mice. Neuronal nitric oxide synthase expression in sciatic nerves was reduced in diabetic mice but was preserved by rosuvastatin. Coadministration of a nitric oxide synthase inhibitor with rosuvastatin attenuated the beneficial effects of rosuvastatin on nerve function and limited the recovery of vasa nervorum and nerve function. In vitro, rosuvastatin inhibited downregulation of neuronal nitric oxide synthase expression induced by high-glucose conditions in cultured Schwann cells. Furthermore, Akt phosphorylation in Schwann cells, downregulated by high-glucose conditions, was also restored by rosuvastatin, consistent with the change of neuronal nitric oxide synthase expression. Akt inhibition independently reduced neuronal nitric oxide synthase expression in Schwann cells in low-glucose cultures. Conclusions - These data indicate that the HMG-CoA reductase inhibitor rosuvastatin has a favorable effect on diabetic neuropathy independent of its cholesterol-lowering effect. Our data provide evidence that this effect may be mediated in part via neuronal nitric oxide synthase/nitric oxide and phosphatidylinositol 3-kinase/Akt-signaling pathways and also suggest that restoration or preservation of the microcirculation of the sciatic nerve may be involved.

Original languageEnglish
Pages (from-to)93-102
Number of pages10
JournalCirculation
Volume112
Issue number1
DOIs
Publication statusPublished - 2005 Jul 5

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Vasa Nervorum
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Nitric Oxide Synthase Type I
Diabetic Neuropathies
Schwann Cells
Peripheral Nervous System Diseases
Sciatic Nerve
Glucose
Down-Regulation
Phosphatidylinositol 3-Kinase
Neural Conduction
Recovery of Function
Diabetes Complications
Microcirculation
Rosuvastatin Calcium
Nitric Oxide Synthase
Cultured Cells
Nitric Oxide
Cholesterol
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Ii, Masaaki ; Nishimura, Hiromi ; Kusano, Kengo F. ; Qin, Gangjian ; Yoon, Youngsup ; Wecker, Andrea ; Asahara, Takayuki ; Losordo, Douglas W. / Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy. In: Circulation. 2005 ; Vol. 112, No. 1. pp. 93-102.
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Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy. / Ii, Masaaki; Nishimura, Hiromi; Kusano, Kengo F.; Qin, Gangjian; Yoon, Youngsup; Wecker, Andrea; Asahara, Takayuki; Losordo, Douglas W.

In: Circulation, Vol. 112, No. 1, 05.07.2005, p. 93-102.

Research output: Contribution to journalArticle

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T1 - Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy

AU - Ii, Masaaki

AU - Nishimura, Hiromi

AU - Kusano, Kengo F.

AU - Qin, Gangjian

AU - Yoon, Youngsup

AU - Wecker, Andrea

AU - Asahara, Takayuki

AU - Losordo, Douglas W.

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N2 - Background - Peripheral neuropathy is a frequent and major complication of diabetes. Methods and Results - Severe peripheral neuropathy developed in type II diabetic mice, characterized by significant slowing of motor and sensory nerve conduction velocities. Rosuvastatin restored nerve vascularity, including vessel size, and nerve function also recovered to the levels of nondiabetic mice. Neuronal nitric oxide synthase expression in sciatic nerves was reduced in diabetic mice but was preserved by rosuvastatin. Coadministration of a nitric oxide synthase inhibitor with rosuvastatin attenuated the beneficial effects of rosuvastatin on nerve function and limited the recovery of vasa nervorum and nerve function. In vitro, rosuvastatin inhibited downregulation of neuronal nitric oxide synthase expression induced by high-glucose conditions in cultured Schwann cells. Furthermore, Akt phosphorylation in Schwann cells, downregulated by high-glucose conditions, was also restored by rosuvastatin, consistent with the change of neuronal nitric oxide synthase expression. Akt inhibition independently reduced neuronal nitric oxide synthase expression in Schwann cells in low-glucose cultures. Conclusions - These data indicate that the HMG-CoA reductase inhibitor rosuvastatin has a favorable effect on diabetic neuropathy independent of its cholesterol-lowering effect. Our data provide evidence that this effect may be mediated in part via neuronal nitric oxide synthase/nitric oxide and phosphatidylinositol 3-kinase/Akt-signaling pathways and also suggest that restoration or preservation of the microcirculation of the sciatic nerve may be involved.

AB - Background - Peripheral neuropathy is a frequent and major complication of diabetes. Methods and Results - Severe peripheral neuropathy developed in type II diabetic mice, characterized by significant slowing of motor and sensory nerve conduction velocities. Rosuvastatin restored nerve vascularity, including vessel size, and nerve function also recovered to the levels of nondiabetic mice. Neuronal nitric oxide synthase expression in sciatic nerves was reduced in diabetic mice but was preserved by rosuvastatin. Coadministration of a nitric oxide synthase inhibitor with rosuvastatin attenuated the beneficial effects of rosuvastatin on nerve function and limited the recovery of vasa nervorum and nerve function. In vitro, rosuvastatin inhibited downregulation of neuronal nitric oxide synthase expression induced by high-glucose conditions in cultured Schwann cells. Furthermore, Akt phosphorylation in Schwann cells, downregulated by high-glucose conditions, was also restored by rosuvastatin, consistent with the change of neuronal nitric oxide synthase expression. Akt inhibition independently reduced neuronal nitric oxide synthase expression in Schwann cells in low-glucose cultures. Conclusions - These data indicate that the HMG-CoA reductase inhibitor rosuvastatin has a favorable effect on diabetic neuropathy independent of its cholesterol-lowering effect. Our data provide evidence that this effect may be mediated in part via neuronal nitric oxide synthase/nitric oxide and phosphatidylinositol 3-kinase/Akt-signaling pathways and also suggest that restoration or preservation of the microcirculation of the sciatic nerve may be involved.

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