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From the Departments of Physiology and Medicine and The
Cardiovascular Research Laboratories,*
UCLA School of
Medicine, Los Angeles, California; Mayo Clinic
Scottsdale,
Scottsdale, Arizona; and the
Department of Physiology and Biophysics,
College of Medicine, University of Illinois at Chicago,
Chicago, Illinois
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 ß1A integrin
(Tacß1A). Using the 
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 ß1 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 ß1 integrin in normal cardiac
function.
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