The α11 integrin mediates fibroblast-extracellular matrix-cardiomyocyte interactions in health and disease

Excessive cardiac interstitial fibrosis impairs normal cardiac function. We have shown that the alpha 11 beta 1 (alpha 11) integrin mediates fibrotic responses to glycated collagen in rat myocardium by a pathway involving transforming growth factor-beta. Little is known of the role of the alpha 11 integrin in the developing mammalian heart. Therefore, we examined the impact of deletion of the alpha 11 integrin in wild-type mice and in mice treated with streptozotocin (STZ) to elucidate the role of the alpha 11 integrin in normal cardiac homeostasis and in the pathogenesis of diabetes-related fibrosis. As anticipated, cardiac fibrosis was reduced in alpha 11 integrin knockout mice (alpha 11(-/-); C57BL/6 background) treated with STZ compared with STZ-treated wild-type mice (P < 0.05). Unexpectedly, diastolic function was impaired in both vehicle and STZ-treated alpha 11(-/-) mice, as shown by the decreased minimum rate of pressure change and prolonged time constant of relaxation in association with increased end-diastolic pressure (all P < 0.05 compared with wild-type mice). Accordingly, we examined the phenotype of untreated alpha 11(-/-) mice, which demonstrated a reduced cardiomyocyte cross-sectional cell area and myofibril thickness (all P < 0.05 compared with wild-type mice) and impaired myofibril arrangement. Immunostaining for desmin and connexin 43 showed abnormal intermediate filament organization at intercalated disks and impaired gap-junction development. Overall, deletion of the alpha 11 integrin attenuates cardiac fibrosis in the mammalian mouse heart and reduces ECM formation as a result of diabetes. Furthermore, alpha 11 integrin deletion impairs cardiac function and alters cardiomyocyte morphology. These findings shed further light on the poorly understood interaction between the fibroblast-cardiomyocyte and the ECM.