Role of Vinculin in Ventricular Wall Function

Abstract

Vinculin (Vcl) is a ubiquitously expressed cytoskeletal protein that localizes at cell adhesion sites in cardiomyocytes. It is a key component in the costamere, which anchors the sarcomeric cytoskeleton to the extracellular matrix via integrins. It has been previously shown that it plays a significant role in mechanotransduction and may affect myocardial mechanical function in a directional-dependent manner. To determine the role of Vcl in regional wall mechanics, cardiac MRI tagging was performed in a cardiac-myocyte-specific vinculin knockout (VclKO) mouse model revealing significant decreases in systolic sheet-normal shear strain (P<0.05) and systolic sheet strain (P<0.05) in KO mice compared with littermate wildtype (WT) controls. In addition, measurements in isolated papillary muscles in heterozygous global vinculin knockout mice showed no difference in isometric fiber tension development consistent with no change in systolic fiber strain in vivo. A finite element model of ventricular mechanics suggested an increase in transverse systolic stress development may explain these observations. We hypothesized that this may be due to an increase in myofilament lattice spacing in the VclKO. Lattice spacing and sarcomere length were measured from optical diffraction patterns generated from FFTs of electron micrographs of VclKO and control hearts. The center-to-center spacing between myosin filaments was 37.6±2.55 nm in barium-contracted VclKO hearts (n=3) compared with 32.9±2.37 nm in WT controls (n=3). In hearts fixed at zero load, this spacing averaged 33.5±1.35 nm in VclKO (n=3) vs. 30.8±0.68 nm in WT (n=3). These results along with sarcomere length measurements suggest Vcl can mediate myofilament architecture and hence directional-dependent systolic force generation. We hypothesize that increasing lattice spacing alters the crossbridge binding angle of myosin heads, increasing the transverse force that they generate. The resulting increase in transverse myofiber stiffness during systole decreases systolic sheet strains.