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

Research output: Contribution to journalArticle

9 Citations (Scopus)

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

Fingerprint

Cardiomyopathies
Cardiac Myocytes
Homeostasis
Dilated Cardiomyopathy
Hypertrophy
Proteins
Heart Failure
Lamin Type A
Contractile Proteins
Gene Regulatory Networks
Cardiomegaly
Gene Expression Profiling
Muscle Cells
Dilatation
Gene Expression
Pressure
Mutation
Genes
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis. / Huang, Zhan Peng; Kataoka, Masaharu; Chen, Jinghai; Wu, Gengze; Ding, Jian; Nie, Mao; Lin, Zhiqiang; Liu, Jianming; Hu, Xiaoyun; Ma, Lixin; Zhou, Bin; Wakimoto, Hiroko; Zeng, Chunyu; Kyselovic, Jan; Deng, Zhong Liang; Seidman, Christine E.; Seidman, J. G.; Pu, William T.; Wang, Da Zhi.

In: Journal of Clinical Investigation, Vol. 125, No. 11, 02.11.2015, p. 4122-4134.

Research output: Contribution to journalArticle

Huang, ZP, 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, ZL, Seidman, CE, Seidman, JG, Pu, WT & Wang, DZ 2015, 'Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis', Journal of Clinical Investigation, vol. 125, no. 11, pp. 4122-4134. https://doi.org/10.1172/JCI82423
Huang, Zhan Peng ; Kataoka, Masaharu ; Chen, Jinghai ; Wu, Gengze ; Ding, Jian ; Nie, Mao ; Lin, Zhiqiang ; Liu, Jianming ; Hu, Xiaoyun ; Ma, Lixin ; Zhou, Bin ; Wakimoto, Hiroko ; Zeng, Chunyu ; Kyselovic, Jan ; Deng, Zhong Liang ; Seidman, Christine E. ; Seidman, J. G. ; Pu, William T. ; Wang, Da Zhi. / Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 11. pp. 4122-4134.
@article{83a25948a58a43d6997fb15bcc7277f1,
title = "Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis",
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.",
author = "Huang, {Zhan Peng} and Masaharu Kataoka and Jinghai Chen and Gengze Wu and Jian Ding and Mao Nie and Zhiqiang Lin and Jianming Liu and Xiaoyun Hu and Lixin Ma and Bin Zhou and Hiroko Wakimoto and Chunyu Zeng and Jan Kyselovic and Deng, {Zhong Liang} and Seidman, {Christine E.} and Seidman, {J. G.} and Pu, {William T.} and Wang, {Da Zhi}",
year = "2015",
month = "11",
day = "2",
doi = "10.1172/JCI82423",
language = "English",
volume = "125",
pages = "4122--4134",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",

}

TY - JOUR

T1 - Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis

AU - Huang, Zhan Peng

AU - Kataoka, Masaharu

AU - Chen, Jinghai

AU - Wu, Gengze

AU - Ding, Jian

AU - Nie, Mao

AU - Lin, Zhiqiang

AU - Liu, Jianming

AU - Hu, Xiaoyun

AU - Ma, Lixin

AU - Zhou, Bin

AU - Wakimoto, Hiroko

AU - Zeng, Chunyu

AU - Kyselovic, Jan

AU - Deng, Zhong Liang

AU - Seidman, Christine E.

AU - Seidman, J. G.

AU - Pu, William T.

AU - Wang, Da Zhi

PY - 2015/11/2

Y1 - 2015/11/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84946771403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946771403&partnerID=8YFLogxK

U2 - 10.1172/JCI82423

DO - 10.1172/JCI82423

M3 - Article

C2 - 26436652

AN - SCOPUS:84946771403

VL - 125

SP - 4122

EP - 4134

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 11

ER -