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(Circulation. 2005;112:93-102.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Neuronal Nitric Oxide Synthase Mediates Statin-Induced Restoration of Vasa Nervorum and Reversal of Diabetic Neuropathy

Masaaki Ii, MD, PhD; Hiromi Nishimura, MD, PhD; Kengo F. Kusano, MD, PhD; Gangjian Qin, MD; Young-sup Yoon, MD, PhD; Andrea Wecker, BS; Takayuki Asahara, MD, PhD; Douglas W. Losordo, MD

From the Division of Cardiovascular Research, Caritas St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass (M.I., K.F.K., G.Q., Y.Y., A.W., T.A., D.W.L.), and Regenerative Medicine, Institute for Biomedical Research and Innovation, Kobe, Japan (H.N., T.A.).

Correspondence to Douglas W. Losordo, MD, Division of Cardiovascular Research, Caritas St Elizabeth’s Medical Center, Tufts University School of Medicine, 736 Cambridge St, Boston, MA 02135. E-mail douglas.losordo{at}tufts.edu

Received October 7, 2004; revision received March 8, 2005; accepted March 11, 2005.

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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