Abstract 1388: Mechanical Properties of the Interaction between Fibronectin and Integrins on Diabetic Cardiomyocytes
Ventricular remodeling is one of the primary adaptive mechanisms in response to long-term mechanical overload in diabetes. In addition to cardiomyocyte hypertrophy, alterations in non-cardiomyocyte 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, we used atomic force microscopy (AFM) for studying cell stiffness and integrin-ECM bond formation in adult mouse cardiomyocytes from normal and type 2 diabetic (db/db) mice. In addition, force and intracellular calcium ([Ca2+]i) measurements on papillary muscle fibers were investigated. AFM probes were coated with ECM protein fibronectin (FN, 2.7 μM) and used to measure adhesion force between integrin receptors and FN by quantifying the unbinding force required to break FN-cardiomyocytes (integrin) bonds. The FN-cardiomyocyte unbinding force in diabetic cardiomyocytes was 38% higher than non-diabetic control cardiomyocytes (58.3 ± 0.3 pN vs 36.5 ± 0.3 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 36% increased in db/db cardiomyocytes. The peaks of the active force, the dynamic rates of contraction and relaxation and [Ca2+]i were significantly (p<0.05) decreased ranged from 22% to 57% in all given stimulating frequency from 1 to 3 Hz, respectively. The peak of Ca2+ release and cardiac contractility stimulated by caffeine were also 44% and 60% lower in db/db papillary fiber, respectively. 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.