Local tenomodulin absence, angiogenesis, and matrix metalloproteinase activation are associated with the rupture of the chordae tendineae cordis.
BACKGROUND
Rupture of the chordae tendineae cordis (CTC) is a well-known cause of mitral regurgitation. Despite its importance, the mechanisms by which the CTC is protected and the cause of its rupture remain unknown. CTC is an avascular tissue. We investigated the molecular mechanisms underlying the avascularity of CTC and the correlation between avascularity and CTC rupture.


RESULTS
We found that tenomodulin, which is a recently isolated antiangiogenic factor, was expressed abundantly in the elastin-rich subendothelial outer layer of normal rodent, porcine, canine, and human CTC. Conditioned medium from cultured CTC interstitial cells strongly inhibited tube formation and mobilization of endothelial cells; these effects were partially inhibited by small-interfering RNA against tenomodulin. The immunohistochemical analysis was performed on 12 normal and 16 ruptured CTC obtained from the autopsy or surgical specimen. Interestingly, tenomodulin was locally absent in the ruptured areas of CTC, where abnormal vessel formation, strong expression of vascular endothelial growth factor-A and matrix metalloproteinases, and infiltration of inflammatory cells were observed, but not in the normal or nonruptured area. In anesthetized open-chest dogs, the tenomodulin layer of tricuspid CTC was surgically filed, and immunohistological analysis was performed after several months. This intervention gradually caused angiogenesis and expression of vascular endothelial growth factor-A and matrix metalloproteinases in the core collagen layer in a time-dependent manner.


CONCLUSIONS
These findings provide evidence that tenomodulin is expressed universally in normal CTC in a concentric pattern and that local absence of tenomodulin, angiogenesis, and matrix metalloproteinase activation are associated with CTC rupture.
Kimura
Naritaka
N
Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, Tokyo, Japan.
Shukunami
Chisa
C
Hakuno
Daihiko
D
Yoshioka
Masatoyo
M
Miura
Shigenori
S
Docheva
Denitsa
D
Kimura
Tokuhiro
T
Okada
Yasunori
Y
Matsumura
Goki
G
Shin'oka
Toshiharu
T
Yozu
Ryohei
R
Kobayashi
Junjiro
J
Ishibashi-Ueda
Hatsue
H
Hiraki
Yuji
Y
Fukuda
Keiichi
K
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D002815:Chordae Tendineae / Q000201:enzymology / Q000293:injuries* / Q000502:physiology*; D004285:Dogs; D004549:Elastin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D006349:Heart Valve Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011817:Rabbits; D012421:Rupture / Q000235:genetics / Q000378:metabolism; D013552:Swine
D008565:Membrane Proteins; C486026:Tnmd protein, mouse; D004549:Elastin; D020782:Matrix Metalloproteinases