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

• Published in: Circulation (New York, N.Y.) N.Y.), 2005-07, Vol.112 (1), p.93-102
• Main Authors: II, Masaaki, NISHIMURA, Hiromi, KUSANO, Kengo F, GANGJIAN QIN, YOON, Young-Sup, WECKER, Andrea, ASAHARA, Takayuki, LOSORDO, Douglas W
• Format: Article
• Language: English
• Subjects: Animals; Associated diseases and complications; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Coronary heart disease; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - drug therapy; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Down-Regulation - drug effects; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Fluorobenzenes - administration & dosage; Fluorobenzenes - pharmacology; Glucose - pharmacology; Heart; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Male; Medical sciences; Mice; Mice, Mutant Strains; Nitric Oxide Synthase Type I - genetics; Nitric Oxide Synthase Type I - physiology; Phosphorylation - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Rosuvastatin Calcium; Schwann Cells - drug effects; Schwann Cells - metabolism; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Treatment Outcome; Vasa Nervorum - drug effects
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.104.511964

Peripheral neuropathy is a frequent and major complication of diabetes. 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. 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.