Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis

Zhan Peng Huang, Masaharu Kataoka, Jinghai Chen, Gengze Wu, Jian Ding, Mao Nie, Zhiqiang Lin, Jianming Liu, Xiaoyun Hu, Lixin Ma, Bin Zhou, Hiroko Wakimoto, Chunyu Zeng, Jan Kyselovic, Zhong Liang Deng, Christine E. Seidman, J. G. Seidman, William T. Pu, Da Zhi Wang

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Abstract

Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.

Original languageEnglish
Pages (from-to)4122-4134
Number of pages13
JournalJournal of Clinical Investigation
Volume125
Issue number11
DOIs
Publication statusPublished - 2015 Nov 2

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Huang, Z. P., Kataoka, M., Chen, J., Wu, G., Ding, J., Nie, M., Lin, Z., Liu, J., Hu, X., Ma, L., Zhou, B., Wakimoto, H., Zeng, C., Kyselovic, J., Deng, Z. L., Seidman, C. E., Seidman, J. G., Pu, W. T., & Wang, D. Z. (2015). Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis. Journal of Clinical Investigation, 125(11), 4122-4134. https://doi.org/10.1172/JCI82423