Fibronectin improves the impaired calcium signaling and myofilament activation in diabetic cardiomyocytes
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AbstractVentricular remodeling is one of the primary adaptive mechanisms in response to long-term mechanical overload in diabetes. In addition to cardiomyocyte hypertrophy, alterations in noncardiomyocyte compartments [e.g. extracellular matrix (ECM)] are an essential process in the remodeling of ventricle during diabetes. Integrins that link the ECM and intracellular cytoskeleton function as mechanotransducers to translate the mechanical force to intracellular signals. We hypothesize that mechanotransduction mechanisms are altered in diabetic cardiomyopathy mouse hearts. To test this hypothesis, force and intracellular calcium ([Ca2+]i) measurements on papillary muscle fibers were investigated in adult mouse cardiomyocytes from normal (non-db) and type 2 diabetic (db/db) mice. In addition, atomic force microscopy (AFM) was used to measure adhesion force between integrin receptors and ECM protein fibronectin (FN) by quantifying the unbinding force required to break FN-cardiomyocytes (integrin) bonds. In db/db mice, the peak active force decreased at 71% or 73% while the peak of [Ca2+]i decreased at 64% and 68% at 1 Hz or 2 Hz. In the presence of the FN (35 nM), active force was increased significantly by 40-50% in db/db mice. Furthermore, increased active force in the presence of FN was associated with 26-42% increase in [Ca2+]iat all giving stimulations of 1 Hz and 2 Hz in db/db mice, respectively. The increased effects on force and [Ca2+]icaused by FN were greater in ventricular muscles from db/db mice than from non-db mice. The unbinding force between FN (2.7 M) coated AFM probes and cardiomyocyte in db/db was 52% higher than non-db (58.3 0.3 pNvs38.6 0.9 pN. p < 0.05). The binding probability of FN-cardiomyocytes, calculated as number of force curves with adhesion / number of total force curves sampled, was significantly reduced by 30% in db/db cardiomyocytes when compared to normal. In addition, the cell stiffness, representing changes in Ca2+ signaling and cytoskeletal reorganization, was 19% increase in db/db cardiomyocytes. The presented data indicate that dynamic changes of the mechanical properties of integrin-ECM interactions may contribute to impaired intracellular Ca2+ signaling and myofilament activation in the diabetic cardiomyopathy.
