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Deletion of RBP-J in adult mice leads to the onset of aortic valve degenerative diseases

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Abstract

Transcription factor RBP-J-mediated Notch signaling has been implicated in several inherited cardiovascular diseases including aortic valve diseases (AVD). But whether Notch signal plays a role in AVD in adults has been unclear. This study aims to test whether the deletion of RBP-J in adult mice would lead to AVD and to investigate the underlying mechanisms. Cre-LoxP-mediated gene deletion was employed to disrupt Notch signal in adult mice. Immunofluorescence and electron microscope observations showed that deletion of RBP-J in adult mice led to early morphological changes of AVD. The size of aortic valve was enlarged. The endothelial homeostasis was perturbed, probably due to the up-regulation of VEGFR2. The endothelial cells exhibited increased proliferation and loose endothelial junctions. The valvular mesenchyme displayed significant fibrosis, consistent with the up-regulation of TGF-β1 and activation of endothelial-mesenchymal transition. We observed melanin-producing cells in aortic valves. The number of melanin-producing cells increased significantly, and their location changed from the mesenchyme to subendothelial layer of valve cusps in RBP-J deficient mice. These results suggest that RBP-J-mediated Notch signaling in aortic valves may be critically involved in valve homeostasis and valve diseases as well. These findings will be helpful for the understanding of the molecular mechanisms of AVD in adults.

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Acknowledgments

We thank K. Rajewsky for Mx-Cre transgenic mice. This work was supported by grants from the National Natural Science Foundation (30600544, 30830067) and the Ministry of Science and Technology of China (2009CB521706).

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Authors and Affiliations

  1. Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #17, Xian, 710032, China

    Zhi Li, Qi-Jun Zheng, Bi-Jun Zhao, Wei Yi, Jin-Zhou Zhang & Ding-Hua Yi

  2. Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xian, 710032, China

    Lei Feng, Chun-Mei Wang & Hua Han

  3. Department of Physiology, Fourth Military Medical University, Xian, 710032, China

    Yue-Min Wang & Hai-Tao Guo

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  1. Zhi Li
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  2. Lei Feng
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  3. Chun-Mei Wang
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  10. Ding-Hua Yi
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Correspondence to Ding-Hua Yi or Hua Han.

Additional information

Z. Li, L. Feng, C.-M. Wang contributed equally to this study.

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Li, Z., Feng, L., Wang, CM. et al. Deletion of RBP-J in adult mice leads to the onset of aortic valve degenerative diseases. Mol Biol Rep 39, 3837–3845 (2012). https://doi.org/10.1007/s11033-011-1162-y

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  • DOI: https://doi.org/10.1007/s11033-011-1162-y

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