Abstract 19552: Exercise-Induced Changes in Mechanotransduction Improve Myocardial Function in a Porcine Model of Chronic Occlusion

Abstract

Introduction: Exercise training has been shown to improve cardiac dysfunction both in patients and animal models of coronary artery disease; however, the underlying cellular and molecular mechanisms have not been completely understood. Transmembrane integrins that connect the extracellular matrix (ECM) and intracellular cytoskeleton are important for mechanotransduction in cardiomyocytes. Hypothesis: The binding probability and adhesion force between integrins-ECM, and their subsequent signaling that is cell stiffness will be increased in the myocytes from exercise-trained animals when compared to the sedentary group. Methods: Ameroid occluders were surgically placed around the proximal left circumflex coronary artery of adult female Yucatan pigs. Twenty-two weeks postoperatively, myocardium was isolated from non-occluded and collateral-dependent regions of sedentary and exercise trained (treadmill run; 5 days/wk for 14 wks) pigs. We used atomic force microscopy for measuring cell stiffness and adhesion force between integrin and fibronectin (FN) in pig cardiomyocytes. In addition, integrins and FN expression were determined. Results: While exercise-trained pigs showed an increase in β1 integrin expression, β3 integrin expression was detected at an increased level in the sedentary myocardium. An increase in the amount of total FN and its fragments were found in the myocardium from collateral-dependent regions of exercise-trained and sedentary pigs when compared to the non-occluded myocardium regions. The peak bond rupture force of FN-integrin (46.4±0.3 pN vs 34.8±0.2 pN), the probability of adhesion (72% vs 54%) and cell stiffness (67.9±4.7 kPa vs 29.0±1.8 kPa) were significantly increased (p<0.05; n=10) in myocytes from exercise-trained pigs when compared to sedentary hearts, which were prevented by function blocking α5 and αv integrin antibodies, respectively. Conclusion: Our data demonstrate that the differences seen in adhesion force, probability and stiffness between the sedentary and exercise-trained myocytes are due to interactions of FN to different integrins, e.g., αvβ3 in sedentary and α5β1 in exercise-trained cells, suggesting potential importance of mechanotransduction pathway for therapeutic development.