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Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis

Nature Medicine volume 12, pages 1151–1159 (2006)Cite this article

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.

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Figure 1: Immunohistochemistry and immunofluorescence staining of Chm-I protein in developing and adult mouse heart.
Figure 2: Abnormal angiogenesis, inflammatory cell infiltration and mineralization in cardiac valves of aged Chm1−/− mice.
Figure 3: Echocardiography of Chm1−/− mouse hearts.
Figure 4: Immunohistochemistry, immunofluorescence staining and in situ hybridization of Chm-I and Vegf-A in sclerotic lesions of aged Apoe−/− mouse hearts.
Figure 5: Expression of Chm-I in VICs and its effect on tube formation, migration and apoptosis in HCAECs.
Figure 6: Histology and immunohistochemistry of cardiac valves from human autopsies and surgical samples.

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Acknowledgements

We thank Y. Nishizaki and S. Kondo for technical support. This study was supported in part by research grants from the Ministry of Education, Science and Culture, Japan, and by the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation.

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Authors and Affiliations

  1. Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Masatoyo Yoshioka, Shinsuke Yuasa, Keisuke Matsumura, Kensuke Kimura, Naritaka Kimura & Keiichi Fukuda

  2. Cardiopulmonary Division, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Masatoyo Yoshioka, Shinsuke Yuasa, Keisuke Matsumura, Kensuke Kimura & Satoshi Ogawa

  3. Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Takayuki Shiomi & Yasunori Okada

  4. Department of Cardiovascular Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Naritaka Kimura, Hankei Shin & Ryohei Yozu

  5. Department of Cellular Differentiation, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Chisa Shukunami & Yuji Hiraki

  6. Division of Diagnostic Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Makio Mukai

  7. Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Masataka Sata

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  1. Masatoyo Yoshioka
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Contributions

This study was designed by K.F.; experiments were performed by M.Y., S.Y., K.M., K.K. and N.K.; the Chm1 knockout mouse and antibody to Chm-I were made by C.S. and Y.H.; surgical specimens were collected by M.M., H.S. and R.Y.; the MMP experiment was performed by T.S. and Y.O.; specimens from Apoe knockout mice were distributed by M.S.; S.O. contributed to the writing of the paper.

Corresponding author

Correspondence to Keiichi Fukuda.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Temporal and spatial expression of Chm1 in rodent and human heart (PDF 2002 kb)

Supplementary Fig. 2

Immunofluorescent staining for Chm-I in middle- and late-stage embryonic mouse heart. (PDF 287 kb)

Supplementary Fig. 3

Antiangiogenic effect of recombinant human CHM-I on HCAECs in vitro. (PDF 224 kb)

Supplementary Fig. 4

MTT assay for VICs. (PDF 982 kb)

Supplementary Fig. 5

Cbfa1-positive cells were detected in vascular areas in VHD. (PDF 189 kb)

Supplementary Fig. 6

Immunohistochemistry of the cardiac valves for MMP-1, -2, -3, -9 and -13 in humans with various VHDs. (PDF 450 kb)

Supplementary Fig. 7

Activated myofibroblasts were detected in vascular areas in VHD. (PDF 279 kb)

Supplementary Fig. 8

The conceptual framework of the role of Chm-I in cardiac valves. (PDF 1790 kb)

Supplementary Methods (PDF 137 kb)

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Yoshioka, M., Yuasa, S., Matsumura, K. et al. Chondromodulin-I maintains cardiac valvular function by preventing angiogenesis. Nat Med 12, 1151–1159 (2006). https://doi.org/10.1038/nm1476

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