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.

Abstract

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

Substances

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

Grant support