title: β1 integrin gene excision in the adult murine cardiac myocyte causes defective mechanical and signaling responses.
abstract: How mechanical signals are transmitted in the cardiac myocyte is poorly understood. In this study, we produced a tamoxifen-inducible mouse model in which β1 integrin could be reduced specifically in the adult cardiomyocyte, so that the function of this integrin could be assessed in the postnatal and mechanically stressed heart. The expression of β1 integrin was reduced to 35% of control levels, but function remained normal at baseline. With aortic constriction, the knockout mice survived but had a blunted hypertrophic response. Integrin knockout myocytes, in contrast to controls, showed reduced integrin-linked kinase expression both at baseline and after hemodynamic stress; focal adhesion kinase expression was reduced after stress. Alterations in multiple signaling pathways were detected in the integrin knockout group after acute and chronic hemodynamic stress. Most remarkably, when we challenged the knockout mice with short-term loading, the robust responses of several kinases (extracellular signal-regulated kinase 1/2, p38, and Akt) evident in control mice were essentially abolished in the knockout mice. We also found that reduction of myocyte β1 integrin expression modified adrenergic-mediated signaling through extracellular signal-regulated kinase, p38, and Akt. Reduction of β1 integrin expression in the mature cardiac myocyte leads to a varied response compared with when this protein is reduced during either the embryonic or perinatal period. These results show that β1 integrin expression is required for proper mechanotransductive and adrenergic responses of the adult heart.
authors.affiliation: Veterans Administration Healthcare, San Diego, California; Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Ruixia
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Veterans Administration Healthcare, San Diego, California; Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Manso
authors.affiliation: Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Veterans Administration Healthcare, San Diego, California; Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Peter
authors.initials: P
authors.lastname: Liao
authors.affiliation: Veterans Administration Healthcare, San Diego, California; Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Sharon
authors.initials: S
authors.lastname: Israeli
authors.affiliation: Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yajima
authors.affiliation: Veterans Administration Healthcare, San Diego, California; Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Uyen
authors.initials: U
authors.lastname: Nguyen
authors.affiliation: Veterans Administration Healthcare, San Diego, California; Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Huang
authors.affiliation: Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.affiliation: Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California.
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: Veterans Administration Healthcare, San Diego, California; Department of Medicine, University of California San Diego, School of Medicine, La Jolla, California. Electronic address: rross@ucsd.edu.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ross
mesh_terms: D000818:Animals; D001011:Aorta; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism; D016923:Cell Death; D003250:Constriction; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D017353:Gene Deletion; D006439:Hemodynamics / Q000502:physiology; D019012:Integrin beta1 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013314:Stress, Mechanical; D000099200:Scaffold Protein ILK
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019012:Integrin beta1; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099200:Scaffold Protein ILK