Calpain inhibitors reduce retinal hypoxia in ischemic retinopathy by improving neovascular architecture and functional perfusion

Biochim Biophys Acta. 2011 Apr;1812(4):549-57. doi: 10.1016/j.bbadis.2010.08.008. Epub 2010 Sep 8.

Abstract

In ischemic retinopathies, underlying hypoxia drives abnormal neovascularization that damages retina and causes blindness. The abnormal neovasculature is tortuous and leaky and fails to alleviate hypoxia, resulting in more pathological neovascularization and retinal damage. With an established model of ischemic retinopathy we found that calpain inhibitors, when administered in moderation, reduced architectural abnormalities, reduced vascular leakage, and most importantly reduced retinal hypoxia. Mechanistically, these calpain inhibitors improved stability and organization of the actin cytoskeleton in retinal endothelial cells undergoing capillary morphogenesis in vitro, and they similarly improved organization of actin cables within new blood vessels in vivo. Hypoxia induced calpain activity in retinal endothelial cells and severely disrupted the actin cytoskeleton, whereas calpain inhibitors preserved actin cables under hypoxic conditions. Collectively, these findings support the hypothesis that hyper-activation of calpains by hypoxia contributes to disruption of the retinal endothelial cell cytoskeleton, resulting in formation of neovessels that are defective both architecturally and functionally. Modest suppression of calpain activity with calpain inhibitors restores cytoskeletal architecture and promotes formation of a functional neovasculature, thereby reducing underlying hypoxia. In sharp contrast to "anti-angiogenesis" strategies that cannot restore normoxia and may aggravate hypoxia, the therapeutic strategy described here does not inhibit neovascularization. Instead, by improving the function of neovascularization to reduce underlying hypoxia, moderate calpain inhibition offers a method for alleviating retinal ischemia, thereby suggesting a new treatment paradigm based on improvement rather than inhibition of new blood vessel growth.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Calpain / antagonists & inhibitors
  • Calpain / chemistry
  • Calpain / metabolism*
  • Catalytic Domain / drug effects
  • Cell Line
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cysteine Proteinase Inhibitors / therapeutic use*
  • Cytoskeleton / drug effects
  • Cytoskeleton / pathology
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Glycoproteins / pharmacology
  • Glycoproteins / therapeutic use*
  • Humans
  • Hypoxia / drug therapy*
  • Hypoxia / pathology
  • Mice
  • Mice, Inbred C57BL
  • Retina / cytology
  • Retina / drug effects
  • Retina / pathology*
  • Retinal Diseases / drug therapy*
  • Retinal Diseases / pathology
  • Retinal Neovascularization / drug therapy*
  • Retinal Neovascularization / pathology
  • Retinal Vessels / drug effects
  • Retinal Vessels / pathology

Substances

  • Actins
  • Cysteine Proteinase Inhibitors
  • Glycoproteins
  • calpain inhibitors
  • Calpain