Published Online
on June 27, 2005

A more recent version of this article appeared on July 5, 2005

This Article Full Text (PDF) All Versions of this Article: 112/1/93    most recent CIRCULATIONAHA.104.511964v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ii, M. Articles by Losordo, D. W. Search for Related Content PubMed PubMed Citation Articles by Ii, M. Articles by Losordo, D. W. Related Collections Angiogenesis Cell signalling/signal transduction Growth factors/cytokines Ischemic biology - basic studies

Submitted on October 7, 2004
Revised on March 8, 2005
Accepted on March 11, 2005

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, and 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.).

^* To whom correspondence should be addressed. E-mail: douglas.losordo{at}tufts.edu.

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.

Key words: diabetes mellitus • nervous system • nitric oxide synthase

This article has been cited by other articles:

				L. M. Belalcazar, V. A. Raghavan, and C. M. Ballantyne Statin-Induced Diabetes: Will It Change Clinical Practice? Diabetes Care, October 1, 2009; 32(10): 1941 - 1943. [Full Text] [PDF]

				Y. L. Tang, W. Zhu, M. Cheng, L. Chen, J. Zhang, T. Sun, R. Kishore, M. I. Phillips, D. W. Losordo, and G. Qin Hypoxic Preconditioning Enhances the Benefit of Cardiac Progenitor Cell Therapy for Treatment of Myocardial Infarction by Inducing CXCR4 Expression Circ. Res., May 22, 2009; 104(10): 1209 - 1216. [Abstract] [Full Text] [PDF]

				J.-O. Jeong, M.-O. Kim, H. Kim, M.-Y. Lee, S.-W. Kim, M. Ii, J.-u. Lee, J. Lee, Y. J. Choi, H.-J. Cho, et al. Dual Angiogenic and Neurotrophic Effects of Bone Marrow-Derived Endothelial Progenitor Cells on Diabetic Neuropathy Circulation, February 10, 2009; 119(5): 699 - 708. [Abstract] [Full Text] [PDF]

				M. S. Kostapanos, H. J. Milionis, and M. S. Elisaf An Overview of the Extra-Lipid Effects of Rosuvastatin Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2008; 13(3): 157 - 174. [Abstract] [PDF]

				R. G Casey, M. Joyce, K. Moore, C. Thompson, P. Fitzgerald, and D. J Bouchier-Hayes Two-week treatment with pravastatin improves ventriculo-vascular haemodynamic interactions in young men with type 1 diabetes Diabetes and Vascular Disease Research, March 1, 2007; 4(1): 53 - 61. [Abstract] [PDF]

				B. D. Wilson, M. Ii, K. W. Park, A. Suli, L. K. Sorensen, F. Larrieu-Lahargue, L. D. Urness, W. Suh, J. Asai, G. A.H. Kock, et al. Netrins Promote Developmental and Therapeutic Angiogenesis Science, August 4, 2006; 313(5787): 640 - 644. [Abstract] [Full Text] [PDF]

				G. Tsivgoulis, K. Spengos, N. Karandreas, M. Panas, A. Kladi, and P. Manta Presymptomatic neuromuscular disorders disclosed following statin treatment. Arch Intern Med, July 24, 2006; 166(14): 1519 - 1524. [Abstract] [Full Text] [PDF]