Mechanical induction of alpha-smooth muscle actin expression involves the rho-rho kinase pathway

In adults the pressure or volume overloaded heart exhibits hypertrophic growth of the myocardium. Increased mechanical loading induces cardiac fibroblasts to express alpha-smooth muscle actin (alpha-SMA), a marker for myofibroblast differentiation. Activated myofibroblasts secrete fibrillar collagens into the interstitium which increase myocardial stiffness. The signaling mechanisms that mediate myofibroblast differentiation and SMA expression are not defined. I examined the role of the Rho-Rho-kinase pathway in force-induced SMA expression in fibroblasts using an in vitro model system that applies static tensile forces (0.65pN/mum2) to integrins of Rat-2 cells via collagen-coated magnetite beads. The data indicate that mechanical forces mediate actin assembly through the Rho-Rho kinase-LIMK-cofilin pathway. Force-mediated actin filament assembly promotes nuclear translocation of MAL and subsequent activation of the SMA promoter to enhance SMA expression.