title: Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis.
abstract: 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.
authors.affiliation: Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Yoshioka
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Yuasa
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsumura
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kimura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shiomi
authors.forename: Naritaka
authors.initials: N
authors.lastname: Kimura
authors.forename: Chisa
authors.initials: C
authors.lastname: Shukunami
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.forename: Makio
authors.initials: M
authors.lastname: Mukai
authors.forename: Hankei
authors.initials: H
authors.lastname: Shin
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yozu
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hiraki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: 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
chemical_list: D020533:Angiogenesis Inhibitors; C489408:Cnmd protein, mouse; D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C068675:CNMD protein, human