Caspase-1 Plays a Critical Role in Accelerating Chronic Kidney Disease-Promoted Neointimal Hyperplasia in the Carotid Artery

J Cardiovasc Transl Res. 2016 Apr;9(2):135-44. doi: 10.1007/s12265-016-9683-3. Epub 2016 Feb 29.

Abstract

To determine whether caspase-1 is critical in chronic kidney disease (CKD)-mediated arterial neointimal hyperplasia (NH), we utilized caspase(-/-) mice and induced NH in carotid artery in a CKD environment, and uremic sera-stimulated human vascular smooth muscle cells (VSMC). We made the following findings: (1) Caspase-1 inhibition corrected uremic sera-mediated downregulation of VSMC contractile markers, (2) CKD-promoted NH was attenuated in caspase(-/-) mice, (3) CKD-mediated downregulation of contractile markers was rescued in caspase null mice, and (4) expression of VSMC migration molecule αvβ3 integrin was reduced in caspase(-/-) tissues. Our results suggested that caspase-1 pathway senses CKD metabolic danger signals. Further, CKD-mediated increase of contractile markers in VSMC and increased expression of VSMC migration molecule αvβ3 integrin in NH formation were caspase-1 dependent. Therefore, caspase-1 is a novel therapeutic target for the suppression of CKD-promoted NH.

Keywords: Caspase-1; Chronic kidney disease (CKD); Neointimal hyperplasia (NH); Vascular inflammation; Vascular smooth muscle cell (VSMC).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Blood Urea Nitrogen
  • Carotid Artery Diseases / enzymology*
  • Carotid Artery Diseases / genetics
  • Carotid Artery Diseases / pathology
  • Carotid Artery Diseases / prevention & control
  • Carotid Artery, Common / enzymology
  • Carotid Artery, Common / pathology
  • Carotid Artery, Common / physiopathology
  • Caspase 1 / deficiency
  • Caspase 1 / genetics
  • Caspase 1 / metabolism*
  • Caspase Inhibitors / pharmacology
  • Cell Movement
  • Cells, Cultured
  • Disease Models, Animal
  • Disease Progression
  • Genotype
  • Humans
  • Hyperplasia
  • Integrin alphaVbeta3 / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Contraction
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / physiopathology
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / enzymology*
  • Myocytes, Smooth Muscle / pathology
  • Neointima*
  • Phenotype
  • Renal Insufficiency, Chronic / blood
  • Renal Insufficiency, Chronic / drug therapy
  • Renal Insufficiency, Chronic / enzymology*
  • Renal Insufficiency, Chronic / genetics

Substances

  • Biomarkers
  • Caspase Inhibitors
  • Integrin alphaVbeta3
  • Caspase 1