The role of costameric proteins in cardiac force transmission and signaling

Costameres are adhesion complexes that link cardiomyocytes to the extracellular matrix (ECM). In the costamere, [beta]1D integrin links the plasma membrane to the ECM, and vinculin creates a bridge to the actin cytoskeleton. In the heart, vinculin and [beta]1D integrin may be important for force transmission and mechanotransduction. The overall goal was to study how disruption of the costamere led to changes in ventricular mechanics, myocardial passive stiffness, and cellular hypertrophic signaling. Decoupling of ECM-cell interactions may alter ventricular regional mechanics particularly in the sheet plane and cross-fiber direction. A technique was developed to calculate 3D ventricular strain distributions in mice using tagged MRI. End-systolic strains in vinculin deficient hearts showed that sheet extension and interlaminar shear were reduced. Structural abnormalities from costamere disruption may also affect force transmission through the costamere, which may manifest as altered material properties of the myocardium. Stretching of vinculin deficient papillary muscles revealed that a defect in the costamere resulted in more compliant tissue. In addition to its role in direct force transmission, the costamere is critical for mechanotransduction. Disruption of [beta]1D integrin function resulted in decreased transverse stretch-induced hypertrophic signaling. In conclusion, abnormal costameres can alter LV mechanics, passive stiffness, and hypertrophic signaling. These changes can contribute to the development of dilated cardiomyopathy and the eventual onset of heart failur