Disruption of integrin function in the murine myocardium leads to perinatal lethality, fibrosis, and abnormal cardiac performance.
The molecular mechanisms that regulate the cardiac hypertrophic response and the progression from compensated hypertrophy to decompensated heart failure have not been thoroughly defined. Alteration in cardiac extracellular matrix is a distinguishing characteristic of these pathological processes. Integrins, cell surface receptors that mediate cellular adhesion to the extracellular matrix, are signaling molecules that possess mechanotransduction properties. Therefore, we hypothesized that integrins are likely candidates to play an important role in cardiac function. To test this hypothesis, transgenic mice were constructed in which normal integrin function was disrupted by expression of a chimeric molecule encoding the transmembrane and extracellular domains of the Tac subunit of the IL-2 receptor, fused to the cytoplasmic domain of beta(1A) integrin (Tacbeta(1A)). Using the alpha myosin heavy chain promoter to target expression of this chimera to the cardiac myocyte, transgenic mice were generated that had varied levels of transgene expression. Multiple transgenic founders that expressed the transgene at high levels, died perinatally and exhibited replacement fibrosis. Lines that survived showed 1) hypertrophic changes concordant with reduction in endogenous beta(1) integrin levels, or 2) reduced basal contractility and relaxation as well as alterations in components of integrin signaling pathways. These data support an important role for beta(1) integrin in normal cardiac function.
Keller
R S
RS
Department of Physiology, UCLA School of Medicine, Center for the Health Sciences, Los Angeles, CA 90095-1751, USA.
Shai
S Y
SY
Babbitt
C J
CJ
Pham
C G
CG
Solaro
R J
RJ
Valencik
M L
ML
Loftus
J C
JC
Ross
R S
RS
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002448:Cell Adhesion; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000502:physiology; D005260:Female; D005313:Fetal Death; D005355:Fibrosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D006439:Hemodynamics; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000502:physiology
D019012:Integrin beta1; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1