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

Am J Physiol Heart Circ Physiol. 2016 Jul 1;311(1):H96-H106. doi: 10.1152/ajpheart.00918.2015. Epub 2016 May 13.


Excessive cardiac interstitial fibrosis impairs normal cardiac function. We have shown that the α11β1 (α11) integrin mediates fibrotic responses to glycated collagen in rat myocardium by a pathway involving transforming growth factor-β. Little is known of the role of the α11 integrin in the developing mammalian heart. Therefore, we examined the impact of deletion of the α11 integrin in wild-type mice and in mice treated with streptozotocin (STZ) to elucidate the role of the α11 integrin in normal cardiac homeostasis and in the pathogenesis of diabetes-related fibrosis. As anticipated, cardiac fibrosis was reduced in α11 integrin knockout mice (α11(-/-); 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 α11(-/-) 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 α11(-/-) 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 α11 integrin attenuates cardiac fibrosis in the mammalian mouse heart and reduces ECM formation as a result of diabetes. Furthermore, α11 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.

Keywords: ECM; cardiac development/function; diabetes; fibrosis; integrins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Size
  • Connexin 43 / metabolism
  • Desmin / metabolism
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetic Cardiomyopathies / genetics
  • Diabetic Cardiomyopathies / metabolism*
  • Diabetic Cardiomyopathies / pathology
  • Diabetic Cardiomyopathies / physiopathology
  • Extracellular Matrix / metabolism*
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibrosis
  • Genotype
  • Integrin alpha Chains / deficiency
  • Integrin alpha Chains / genetics
  • Integrin alpha Chains / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Myofibrils / metabolism
  • Myofibrils / pathology
  • Phenotype
  • Signal Transduction
  • Streptozocin
  • Stroke Volume
  • Ventricular Dysfunction, Left / genetics
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Function, Left
  • Ventricular Pressure
  • Ventricular Remodeling


  • Connexin 43
  • Desmin
  • GJA1 protein, mouse
  • Integrin alpha Chains
  • integrin alpha11, mouse
  • Streptozocin

Grant support