Statins decrease dendritic arborization in rat sympathetic neurons by blocking RhoA activation.
Clinical and experimental evidence suggest that statins decrease sympathetic activity, but whether peripheral mechanisms involving direct actions on post-ganglionic sympathetic neurons contribute to this effect is not known. Because tonic activity of these neurons is directly correlated with the size of their dendritic arbor, we tested the hypothesis that statins decrease dendritic arborization in sympathetic neurons. Oral administration of atorvastatin (20 mg/kg/day for 7 days) significantly reduced dendritic arborization in vivo in sympathetic ganglia of adult male rats. In cultured sympathetic neurons, statins caused dendrite retraction and reversibly blocked bone morphogenetic protein-induced dendritic growth without altering cell survival or axonal growth. Supplementation with mevalonate or isoprenoids, but not cholesterol, attenuated the inhibitory effects of statins on dendritic growth, whereas specific inhibition of isoprenoid synthesis mimicked these statin effects. Statins blocked RhoA translocation to the membrane, an event that requires isoprenylation, and constitutively active RhoA reversed statin effects on dendrites. These observations that statins decrease dendritic arborization in sympathetic neurons by blocking RhoA activation suggest a novel mechanism by which statins decrease sympathetic activity and protect against cardiovascular and cerebrovascular disease.
Kim
Woo-Yang
WY
Department of Pharmacology and Toxicology, SUNY, Buffalo, New York, USA.
Gonsiorek
Eugene A
EA
Barnhart
Chris
C
Davare
Monika A
MA
Engebose
Abby J
AJ
Lauridsen
Holly
H
Bruun
Donald
D
Lesiak
Adam
A
Wayman
Gary
G
Bucelli
Robert
R
Higgins
Dennis
D
Lein
Pamela J
PJ
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D019485:Bone Morphogenetic Proteins / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism / Q000494:pharmacology; D054876:Prenylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013729:Terpenes / Q000037:antagonists & inhibitors / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013729:Terpenes; D020742:rhoA GTP-Binding Protein; D008798:Mevalonic Acid