Abstract 3852: Fibronectin Increases Mouse Cardiac Contractility via Alpha (5) Beta (1) Integrin
The extracellular matrix proteins-integrins-cytoskeletal axis plays a central role in mechano-transduction during normal development and in response to mechanical forces associated with physiological and pathological states. However, how mechanically transduced signals affect myofilament function in cardiac muscle has not been understood. We hypothesized that fibronectin (FN) would increase cardiac contractile function by modulating intracellular Ca2+ concentration ([Ca2+]i) and/or myofilament activation processes, Force-Ca2+ relationships were determined in intact murine papillary muscles. Results demonstrated that soluble FN (100 nM) increased active force significantly by 16% to 54% from 1 to 9 Hz stimulation (n=9, p<0.05) and also increased the rate of maximum force generation and relaxation. Increased active force (Fig A⇓ at 2 Hz stimulation) in the presence of FN was associated with 12–33 % increase in [Ca2+]i and a 20 –50% increase in the force/[Ca 2+]i ratio indicating enhanced myofilament Ca2+ sensitivity. Papillary muscles pre-treated with a function-blocking antibody to α5β1 integrin (60 nM) prevented FN-induced changes in force and [Ca2+]i, whereas a blocking antibody to α3β1 integrin (60 nM) had no effect. FN-enhanced force and [Ca2+]i were inhibited by pretreatment with L-type Ca2+ channel blocker verapamil (2.5 μM) or protein kinase A (PKA) inhibitor 14 –22 amide (1 μM) (Fig B⇓ at 2 Hz). Thus, these data suggest that FN acting via α5β1 integrin increases force production in papillary muscles associated with changes in [Ca2+]i through Ca2+ entry and PKA activation by modulating myofilament activation processes.