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.
authors.forename: Zhan-Peng
authors.initials: ZP
authors.lastname: Huang
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kataoka
authors.forename: Jinghai
authors.initials: J
authors.lastname: Chen
authors.forename: Gengze
authors.initials: G
authors.lastname: Wu
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Mao
authors.initials: M
authors.lastname: Nie
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.forename: Jianming
authors.initials: J
authors.lastname: Liu
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Hu
authors.forename: Lixin
authors.initials: L
authors.lastname: Ma
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Chunyu
authors.initials: C
authors.lastname: Zeng
authors.forename: Jan
authors.initials: J
authors.lastname: Kyselovic
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Deng
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: William T
authors.initials: WT
authors.lastname: Pu
authors.forename: Da-Zhi
authors.initials: DZ
authors.lastname: Wang
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000502:physiology; D006332:Cardiomegaly / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D056970:Co-Repressor Proteins; D004195:Disease Models, Animal; D018450:Disease Progression; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D053263:Gene Regulatory Networks; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology; D006706:Homeostasis; D006801:Humans; D034904:Lamin Type A / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011312:Pressure / Q000009:adverse effects; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D059467:Transcriptome; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D034904:Lamin Type A; C576142:Lmna protein, mouse; C559899:MLIP protein, mouse; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D019703:Calcineurin