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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomarkers / metabolism
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Blood Urea Nitrogen
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Carotid Artery Diseases / enzymology*
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Carotid Artery Diseases / genetics
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Carotid Artery Diseases / pathology
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Carotid Artery Diseases / prevention & control
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Carotid Artery, Common / enzymology
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Carotid Artery, Common / pathology
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Carotid Artery, Common / physiopathology
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Caspase 1 / deficiency
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Caspase 1 / genetics
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Caspase 1 / metabolism*
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Caspase Inhibitors / pharmacology
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Cell Movement
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Cells, Cultured
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Disease Models, Animal
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Disease Progression
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Genotype
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Humans
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Hyperplasia
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Integrin alphaVbeta3 / metabolism
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Mice, Inbred C57BL
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Mice, Knockout
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Muscle Contraction
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / enzymology*
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Muscle, Smooth, Vascular / pathology
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Muscle, Smooth, Vascular / physiopathology
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / enzymology*
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Myocytes, Smooth Muscle / pathology
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Neointima*
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Phenotype
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Renal Insufficiency, Chronic / blood
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Renal Insufficiency, Chronic / drug therapy
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Renal Insufficiency, Chronic / enzymology*
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Renal Insufficiency, Chronic / genetics
Substances
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Biomarkers
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Caspase Inhibitors
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Integrin alphaVbeta3
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Caspase 1