Vascular endothelial growth factor mediates atorvastatin-induced mammalian achaete-scute homologue-1 gene expression and neuronal differentiation after stroke in retired breeder rats.
Neurogenesis declines with advancing age. The mammalian achaete-scute homologue-1 encodes a basic helix-loop-helix transcription factor, which controls neuronal differentiation. In this study, we first tested whether atorvastatin treatment enhances neurological functional outcome and neuronal differentiation after stroke in retired breeder 12 month rats. Rats were subjected to middle cerebral artery occlusion and treated with or without atorvastatin (3 mg/kg) for 7 days. Atorvastatin significantly increased expression of mammalian achaete-scute homologue-1, beta-tubulin III, and vascular endothelial growth factor in the ischemic brain, and concomitantly improved functional outcome compared with middle cerebral artery occlusion control rats. Increased neurogenesis significantly correlated with functional recovery after stroke. To further investigate the mechanisms of atorvastatin-induced neuronal differentiation, experiments were performed on neurospheres derived from retired breeder rat subventricular zone cells. Atorvastatin increased neuronal differentiation and upregulated vascular endothelial growth factor and mammalian achaete-scute homologue-1 gene expression in cultured neurospheres. Vascular endothelial growth factor-treated neurospheres significantly increased mammalian achaete-scute homologue-1 and beta-tubulin III expression. Inhibition of vascular endothelial growth factor decreased atorvastatin-induced mammalian achaete-scute homologue-1 and beta-tubulin III expression. These data indicate that atorvastatin increases neuronal differentiation in retired breeder rats. In addition, atorvastatin upregulation of vascular endothelial growth factor expression, influences mammalian achaete-scute homologue-1 transcription factor, which in turn, facilitates an increase in subventricular zone neuronal differentiation. These atorvastatin-mediated molecular events may contribute to the improved functional outcome in retired breeder rats subjected to stroke.
Chen
J
J
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Zacharek
A
A
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Li
A
A
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Zhang
C
C
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Ding
J
J
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Roberts
C
C
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Lu
M
M
Department of Biostatistics and Research Epidemiology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Kapke
A
A
Department of Biostatistics and Research Epidemiology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Chopp
M
M
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA; Department of Physics, Oakland University, Rochester, MI 48309, USA. Electronic address: chopp@neuro.hfh.edu.
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000069059:Atorvastatin; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D006538:Heptanoic Acids / Q000008:administration & dosage*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D007150:Immunohistochemistry / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D011758:Pyrroles / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014404:Tubulin / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000502:physiology*
D000906:Antibodies; D000069059:Atorvastatin; D051792:Basic Helix-Loop-Helix Proteins; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D012333:RNA, Messenger; D014404:Tubulin; D042461:Vascular Endothelial Growth Factor A; C499318:Ascl1 protein, rat