Abstract 1673: Disruption of Chondromodulin-I Gene, a Potent Angioinhibitory Factor, Causes Aortic Valve Stenosis in Mice
[Introduction] Cardiac valves are well known avascular tissue, although their avascularity is abrogated in several valvular heart diseases (VHD). We recently reported that cardiac valves express chondromodulin-I (chm-I), an angioinhibitory factor purified from fetal bovine epiphyseal cartilage. The purpose of this study was to demonstrate whether gene targeting of chm-I affects valvular abnormality, and in particular, whether or not it can cause VHD in mice.
[Methods and Results] (1) Gene targeting of chm-I was examined using C57BL/6 mice; the homozygous (chm-1-/-) mice and age-matched wildtype littermates (WT) were used for the experiment. (2) Cardiac valves of 8-week-old mice were histologically similar to WT. The aortic valves (AV) of old age (90 weeks) chm-1-/- mice were significantly more bulky and the density of valvular interstitial cells was more sparse than in WT. The mean thickness of AV gradually increased after 32 weeks, and reached a thickness of 1.8-fold that of WT at 90 weeks. No significant morphological changes were observed in mitral valve or other valves. (3) Cardiac valves displayed de novo capillary-like structures and were chM-I negative and VEGF-A positive in chm-1-/- mice. VEGF expression was not observed in the young adult, but was up-regulated in aged mice. Cells forming capillary-like structures were vWF positive. (4) von Kossa staining revealed calcium deposits, MAC-1 staining showed the presence of inflammatory cells, and Sudan IV staining revealed that affected valves were laden with lipid in chm-1-/- mice but not WT. (5) The capillary number in chm-1-/- mice was 13.8 times higher than in WT. Changes in these characteristics were not remarkable in other valves. (6) Echocardiography revealed thickened or calcified AVswinging with slight acoustic shadowing. A color Doppler study showed a mosaic turbulent jet distal to AV in chm-1-/- mice but not in WT. There was no significant difference between WT and chm-1-/- mice in left ventricular wall thickness, end-diastolic and end-systolic dimensions, and ejection fraction.
[Conclusion] Disruption of chm-I causes valvular degeneration leading to aortic valve stenosis in mice. ChM-I plays a key role in maintaining the valvular function by preventing angiogenesis in the cardiac valves.