title: Targeted ablation of PINCH1 and PINCH2 from murine myocardium results in dilated cardiomyopathy and early postnatal lethality.
abstract: BACKGROUND
  PINCH proteins are 5 LIM domain-only adaptor proteins that function as key components of the integrin signaling pathway and play crucial roles in multiple cellular processes. Two PINCH proteins, PINCH1 and PINCH2, have been described in mammals and share high homology. Both PINCH1 and PINCH2 are ubiquitously expressed in most tissues and organs, including myocardium. Cardiac-specific PINCH1 knockout or global PINCH2 knockout mice exhibit no basal cardiac phenotype, which may reflect a redundant role for these 2 PINCH proteins in myocardium. A potential role for PINCH proteins in myocardium remains unknown.
  
  
  RESULTS
  To define the role of PINCH in myocardium, we generated mice that were doubly homozygous null for PINCH1 and PINCH2 in myocardium. Resulting mutants were viable at birth but developed dilated cardiomyopathy and died of heart failure within 4 weeks. Mutant hearts exhibited disruptions of intercalated disks and costameres accompanied by fibrosis. Furthermore, multiple cell adhesion proteins exhibited reduced expression and were mislocalized. Mutant cardiomyocytes were significantly smaller and irregular in size. In addition, we observed that the absence of either PINCH1 or PINCH2 in myocardium leads to exacerbated cardiac injury and deterioration in cardiac function after myocardial infarction.
  
  
  CONCLUSIONS
  These results demonstrate essential roles for PINCHs in myocardial growth, maturation, remodeling, and function and highlight the importance of studying the role of PINCHs in human cardiac injury and cardiomyopathy.
authors: Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0613, USA.
authors: Xingqun
authors: X
authors: Liang
authors: Yunfu
authors: Y
authors: Sun
authors: Maoqing
authors: M
authors: Ye
authors: Maria C
authors: MC
authors: Scimia
authors: Hongqiang
authors: H
authors: Cheng
authors: Jody
authors: J
authors: Martin
authors: Gang
authors: G
authors: Wang
authors: Ann
authors: A
authors: Rearden
authors: Chuanyue
authors: C
authors: Wu
authors: Kirk L
authors: KL
authors: Peterson
authors: Henry C
authors: HC
authors: Powell
authors: Sylvia M
authors: SM
authors: Evans
authors: Ju
authors: J
authors: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002448:Cell Adhesion / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism / Q000401:mortality; D016023:Integrins / Q000378:metabolism; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000099200:Scaffold Protein ILK
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D016023:Integrins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D000099200:Scaffold Protein ILK; C490232:Lims1 protein, mouse; C490234:Lims2 protein, mouse