Neuronal nitric oxide synthase mediates statin-induced restoration of vasa nervorum and reversal of diabetic neuropathy.
BACKGROUND
Peripheral neuropathy is a frequent and major complication of diabetes.


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.
Division of Cardiovascular Research, Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St, Boston, MA 02135, USA.
Masaaki
M
Ii
Hiromi
H
Nishimura
Kengo F
KF
Kusano
Gangjian
G
Qin
Young-sup
YS
Yoon
Andrea
A
Wecker
Takayuki
T
Asahara
Douglas W
DW
Losordo
D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D015536:Down-Regulation / Q000187:drug effects; D005464:Fluorobenzenes / Q000008:administration & dosage / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D016896:Treatment Outcome; D014650:Vasa Nervorum / Q000187:drug effects*
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D052248:Nitric Oxide Synthase Type I; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose