Local Tenomodulin Absence, Angiogenesis, and Matrix Metalloproteinase Activation Are Associated With the Rupture of the Chordae Tendineae Cordis

Abstract

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. Methods and 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.

Platelet-released growth factors can accelerate tenocyte proliferation and activate the anti-oxidant response element

“…Tenomodulin is a structural protein that has been shown to be essential for tendon maturation (Docheva et al 2005) and maintenance of tendon integrity as shown for tendon cells in the eye (Kimura et al 2008). Tendon tissue principally is very little vascularised and tenomodulin seems a critical factor that regulates the neoformation of vessels (Shukunami et al 2001).…”

Scleraxis and osterix antagonistically regulate tensile force-responsive remodeling of the periodontal ligament and alveolar bone

“…We reported that Scx positively regulates the expression of Tnmd, which has anti-angiogenic activity in its C-terminal cysteinerich domain (Kimura et al, 2008;Oshima et al, 2004). In contrast to ligaments responsible for bone-to-bone connections, the PDL, localized between the alveolar bone and the cementum of the tooth, is exceptionally well vascularized, reflecting the high metabolic turnover of cellular and extracellular constituents.…”

Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents

“…In contrast, angiogenesis and VEGF expression are increased in calcified aortic valves (21,22). Previously, we showed that chondromodulin I (encoded by Lect1) and tenomodulin, angioinhibitory factors expressed in the cartilage and tendon, respectively, were expressed in the cardiac valves and chordae tendineae cordis (23,24), respectively. Whereas chondromodulin I was expressed in the normal cardiac valves, its expression was diminished in areas of angiogenesis in the degenerated valves of human VHD.…”