De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury.
The role of transient receptor potential M4 (Trpm4), an unusual member of the Trp family of ion channels, is poorly understood. Using rodent models of spinal cord injury, we studied involvement of Trpm4 in the progressive expansion of secondary hemorrhage associated with capillary fragmentation, the most destructive mechanism of secondary injury in the central nervous system. Trpm4 mRNA and protein were abundantly upregulated in capillaries preceding their fragmentation and formation of petechial hemorrhages. Trpm4 expression in vitro rendered COS-7 cells highly susceptible to oncotic swelling and oncotic death following ATP depletion. After spinal cord injury, in vivo gene suppression in rats treated with Trpm4 antisense or in Trpm4(-/-) mice preserved capillary structural integrity, eliminated secondary hemorrhage, yielded a threefold to fivefold reduction in lesion volume and produced a substantial improvement in neurological function. To our knowledge, this is the first example of a Trp channel that must undergo de novo expression for manifestation of central nervous system pathology.
Gerzanich
Volodymyr
V
Department of Neurosurgery, University of Maryland School of Medicine, 22 South Greene Street, Suite S12D, Baltimore, Maryland 21201-1595, USA.
Woo
S Kyoon
SK
Vennekens
Rudi
R
Tsymbalyuk
Orest
O
Ivanova
Svetlana
S
Ivanov
Alexander
A
Geng
Zhihua
Z
Chen
Zheng
Z
Nilius
Bernd
B
Flockerzi
Veit
V
Freichel
Marc
M
Simard
J Marc
JM
D000818:Animals; D001483:Base Sequence; D016923:Cell Death; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006470:Hemorrhage / Q000209:etiology / Q000235:genetics*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013119:Spinal Cord Injuries / Q000150:complications / Q000235:genetics* / Q000473:pathology; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D016376:Oligonucleotides, Antisense; D050053:TRPM Cation Channels; C500239:TRPM4 protein, rat