Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis.
The avascularity of cardiac valves is abrogated in several valvular heart diseases (VHDs). This study investigated the molecular mechanisms underlying valvular avascularity and its correlation with VHD. Chondromodulin-I, an antiangiogenic factor isolated from cartilage, is abundantly expressed in cardiac valves. Gene targeting of chondromodulin-I resulted in enhanced Vegf-A expression, angiogenesis, lipid deposition and calcification in the cardiac valves of aged mice. Echocardiography showed aortic valve thickening, calcification and turbulent flow, indicative of early changes in aortic stenosis. Conditioned medium obtained from cultured valvular interstitial cells strongly inhibited tube formation and mobilization of endothelial cells and induced their apoptosis; these effects were partially inhibited by chondromodulin-I small interfering RNA. In human VHD, including cases associated with infective endocarditis, rheumatic heart disease and atherosclerosis, VEGF-A expression, neovascularization and calcification were observed in areas of chondromodulin-I downregulation. These findings provide evidence that chondromodulin-I has a pivotal role in maintaining valvular normal function by preventing angiogenesis that may lead to VHD.
Yoshioka
Masatoyo
M
Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Yuasa
Shinsuke
S
Matsumura
Keisuke
K
Kimura
Kensuke
K
Shiomi
Takayuki
T
Kimura
Naritaka
N
Shukunami
Chisa
C
Okada
Yasunori
Y
Mukai
Makio
M
Shin
Hankei
H
Yozu
Ryohei
R
Sata
Masataka
M
Ogawa
Satoshi
S
Hiraki
Yuji
Y
Fukuda
Keiichi
K
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology*; D017077:Culture Media, Conditioned / Q000378:metabolism; D004452:Echocardiography; D006349:Heart Valve Diseases / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D008875:Middle Aged; D008943:Mitral Valve / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D051381:Rats; D017208:Rats, Wistar
D020533:Angiogenesis Inhibitors; C489408:Cnmd protein, mouse; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C068675:CNMD protein, human