Syndecan-1 amplifies angiotensin II-induced cardiac fibrosis.
Syndecan-1 (Synd1) is a transmembrane heparan sulfate proteoglycan that functions as a coreceptor for various growth factors and modulates signal transduction. The present study investigated whether Synd1, by affecting growth factor signaling, may play a role in hypertension-induced cardiac fibrosis and dysfunction. Expression of Synd1 was increased significantly in mouse hearts with angiotensin II-induced hypertension, which was spatially related to cardiac fibrosis. Angiotensin II significantly impaired fractional shortening and induced cardiac fibrosis in wild-type mice, whereas these effects were blunted in Synd1-null mice. Angiotensin II significantly increased cardiac expression of connective tissue growth factor and collagen type I and III in wild-type mice, which was blunted in Synd1-null mice. These findings were confirmed in vitro, where angiotensin II induced the expression of both connective tissue growth factor and collagen I in fibroblasts. The absence of Synd1 in either Synd1-null fibroblasts, after knockdown of Synd1 by short hairpin RNA, or after inhibition of heparan sulfates by protamine attenuated this increase, which was associated with reduced phosphorylation of Smad2. In conclusion, loss of Synd1 reduces cardiac fibrosis and dysfunction during angiotensin II-induced hypertension.
Schellings
Mark W M
MW
Department of Cardiology, Cardiovascular Research Institute Maastricht, University Hospital Maastricht, Maastricht, The Netherlands.
Vanhoutte
Davy
D
van Almen
Geert C
GC
Swinnen
Melissa
M
Leenders
Joost J G
JJ
Kubben
Nard
N
van Leeuwen
Rick E W
RE
Hofstra
Leo
L
Heymans
Stephane
S
Pinto
Yigal M
YM
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology; D005786:Gene Expression Regulation; D006973:Hypertension / Q000139:chemically induced / Q000150:complications; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000473:pathology*; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051899:Smad2 Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D051899:Smad2 Protein; D053668:Syndecan-1; D000804:Angiotensin II