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Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis
Zhan-Peng Huang, … , William T. Pu, Da-Zhi Wang
Zhan-Peng Huang, … , William T. Pu, Da-Zhi Wang
Published October 5, 2015
Citation Information: J Clin Invest. 2015;125(11):4122-4134. https://doi.org/10.1172/JCI82423.
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Research Article Cardiology Article has an altmetric score of 12

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

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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.

Authors

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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Figure 1

Loss of CIP accelerates the progress from hypertrophy to heart failure during cardiac remodeling.

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Loss of CIP accelerates the progress from hypertrophy to heart failure d...
(A) qRT-PCR detection of the expression of human CIP transcripts in the hearts of patients with dilated cardiomyopathy (DCM). n = 5–10 for each group. (B) Western blot detection of the expression of mouse CIP proteins in dilated cardiomyopathy and control mouse hearts. GAPDH was used as a control. (C) Expression of CIP mRNA (n = 3 for each group) and protein in CIP-KO hearts detected by qRT-PCR and Western blot, respectively. Arrowheads mark multiple CIP protein products encoded by CIP mRNA splicing isoforms. (D) LV internal dimension at end-diastole (LVID;d) and FS of CIP-KO and control mice at indicated ages. (E) Gross heart morphology and H&E staining of CIP-KO and control hearts 4 weeks after TAC or sham operation. Scale bar: 2 mm. (F) LV posterior wall thickness at end-diastole (LVPW;d), LV internal dimension at end-diastole, and FS of TAC- or sham-operated CIP-KO and control mice. (G) Heart cross sections were stained with wheat germ agglutinin, and cardiomyocyte cross-sectional area was quantified. Scale bar: 50 μm. (H) Fast green and Sirius red staining of TAC- or sham-operated CIP-KO and control hearts. The fibrotic area was quantified. Scale bar: 1.5 mm. (I) qRT-PCR detection of expression of hypertrophy marker genes. n = 3–5 for each group. *P < 0.05, **P < 0.01, 1-way ANOVA with post-hoc Tukey’s test. The n number for each group is indicated.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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