Integrins are transmembrane mechanoreceptors transmitting outside-in-signaling in cells. Using a combination of conventional and conditional gene targeting, a ventricle-specific conditional integrin â1 gene knockout was induced in mice. They were born viable and expressed 27%±3.4 and 10%±1.9 (n=12) of control levels of â1 Integrin at the age of 1 and 3 months.

These mice underwent aortic constriction (TAC) and sham operations and were examined 2, 7 and 30 days later by echocardiography and hemodynamic analyses. The â1 integrin knockout led to dilated cardiac myopathy but not to a compensatory hypertrophic response as in controls.

Investigation of downstream signaling revealed activation of the p38 MAP Kinase, Erk 1 and 2, FAK and phosphorylation of c-Src in wild-type TAC hearts, which was blunted in the knockouts. Microarray analyses (n=6) 7 days after TAC revealed a more than 2-fold up-regulation of Collagen (8.11±2.3), Fibronectin (2.32±0.94), SPARC (3.78±0.12), Timp2, (2.23±0.98), whereas this up-regulation was abolished in knockout mice.

We conclude that signaling downstream of integrin beta1 is mediated by the MAPK, FAK and c-Src pathways leading to an up-regulation of extracelluar matrix components necessary for the compensatory response of the heart.