Endothelial S100A1 modulates vascular function via nitric oxide.
S100A1, a Ca(2+)-binding protein of the EF-hand type, is known to modulate sarcoplasmic reticulum Ca(2+) handling in skeletal muscle and cardiomyocytes. Recently, S100A1 has been shown to be expressed in endothelial cells (ECs). Because intracellular Ca(2+) ([Ca(2+)](i)) transients can be involved in important EC functions and endothelial NO synthase activity, we sought to investigate the impact of endothelial S100A1 on the regulation of endothelial and vascular function. Thoracic aortas from S100A1 knockout mice (SKO) showed significantly reduced relaxation in response to acetylcholine compared with wild-type vessels, whereas direct vessel relaxation using sodium nitroprusside was unaltered. Endothelial dysfunction attributable to the lack of S100A1 expression could also be demonstrated in vivo and translated into hypertension of SKO. Mechanistically, both basal and acetylcholine-induced endothelial NO release of SKO aortas was significantly reduced compared with wild type. Impaired endothelial NO production in SKO could be attributed, at least in part, to diminished agonist-induced [Ca(2+)](i) transients in ECs. Consistently, silencing endothelial S100A1 expression in wild type also reduced [Ca(2+)](i) and NO generation. Moreover, S100A1 overexpression in ECs further increased NO generation that was blocked by the inositol-1,4,5-triphosphate receptor blocker 2-aminoethoxydiphenylborate. Finally, cardiac endothelial S100A1 expression was shown to be downregulated in heart failure in vivo. Collectively, endothelial S100A1 critically modulates vascular function because lack of S100A1 expression leads to decreased [Ca(2+)](i) and endothelial NO release, which contributes, at least partially, to impaired endothelium-dependent vascular relaxation and hypertension in SKO mice. Targeting endothelial S100A1 expression may, therefore, be a novel therapeutic means to improve endothelial function in vascular disease or heart failure.
Pleger
Sven T
ST
Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Harris
David M
DM
Shan
Changguang
C
Vinge
Leif E
LE
Chuprun
J Kurt
JK
Berzins
Brett
B
Pleger
Wiebke
W
Druckman
Charles
C
Völkers
Mirko
M
Heierhorst
Jörg
J
Øie
Erik
E
Remppis
Andrew
A
Katus
Hugo A
HA
Scalia
Rosario
R
Eckhart
Andrea D
AD
Koch
Walter J
WJ
Most
Patrick
P
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D009418:S100 Proteins / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D053496:Inositol 1,4,5-Trisphosphate Receptors; D009418:S100 Proteins; C110294:S100A1 protein; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D000109:Acetylcholine; D002118:Calcium