Abstract 389: Ventricular Myocyte-Restricted Targeting of Integrin Beta1 Abolishes Compensatory Cardiac Hypertrophy Due to Altered Expression of Extracellular Matrix Components
Integrins are transmembrane receptors transmitting mechanical signals from the extracellular matrix (ECM) to the cytoskeleton (outside-in-signaling). Many molecular defects in the links between cytoskeleton and ECM are known to induce cardiomyopathies. We hypothesized that integrin-mediated signaling is required for the compensatory hypertrophy after transveral aortic constriction (TAC). Using a combination of conventional and conditional myosin light chain-2 cre/loxP gene targeting, a ventricle-specific integrin beta1 gene knockout was induced with 12%±1.9 (n=12) of control levels of Integrin beta1 protein at the age of 3 months. TAC and sham-operated three months old knock out mice and wild type mice were examined at day 2, day 7 and one month after operation by echocardiography and hemodynamic analyses. TAC in knockout mice led to a dilated cardiomyopathy but not to a compensatory hypertrophy as observed in controls suggesting intolerance to pressure overload. Investigation of downstream signaling revealed significant activation of the p38 Mitogen-Activated Protein Kinase (MAPK), the Extracellular signal-Regulated Kinases 1 and 2 (Erk 1/2), Focal Adhesion Kinase (FAK), and tyrosine-phosphorylation of c-Src in wild type TAC hearts, which was blunted in knockout mice. Microarrays probing for a total of 96 cell adhesion and ECM genes identified various genomic targets of Integrin beta1-mediated signaling: In wild-type mice, 7 days after TAC 11 ECM genes were up-regulated more than 2-fold (n=6), e.g. Collagen (8.11 ± 2.2), Fibronectin (2.32 ± 0.94), secreted protein, acidic and rich in cysteine (SPARC, 3.78 ± 0.12), and Tissue inhibitor of metalloproteinase 2 (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. The cardiomyocyte-specific ablation of integrin beta 1 uncouples these signaling processes and opens the way to cardiac dilation.