Abstract
Objective:
Vascular calcification significantly increases cardiovascular morbidity and mortality. We recently reported that the deficiency of cartilage oligomeric matrix protein (COMP) leads to vascular mineralization. We characterized the COMP-degrading metalloproteinase, a disintegrin and metalloproteinase with thrombospondin motifs-7 (ADAMTS-7). Here, we tested whether ADAMTS-7 facilitates vascular calcification.
Methods and results:
ADAMTS-7 expression was markedly upregulated in calcifying rat vascular smooth muscle cells (VSMCs) in vitro, calcified arteries of rats with chronic renal failure in vivo, and radial arteries of uraemic patients. Silencing of ADAMTS-7 markedly reduced COMP degradation and ameliorated VSMC calcification, whereas ectopic expression of ADAMTS-7 greatly enhanced COMP degradation and exacerbated mineralization. The transcriptional activity of ADAMTS-7 promoter was not altered by high phosphate. We used bioinformatics and quantitative polymerase chain reaction analysis to demonstrate that high-phosphate upregulated ADAMTS-7 mRNA and protein via miR-29a/b repression, which directly targeted the 3' untranslated region of ADAMTS-7 in VSMCs. MicroRNA (MiR)-29a/b mimic markedly inhibited but miR-29a/b inhibitor greatly enhanced high-phosphate-induced ADAMTS-7 expression, COMP degradation, and subsequent VSMC calcification. ADAMTS-7 silencing significantly diminished miR-29a/b repression-exaggerated VSMC calcification.
Conclusions:
Our data reveal a novel mechanism by which ADAMTS-7 upregulation by miR-29a/b repression mediates vascular calcification, which may shed light on preventing cardiovascular morbidity and mortality.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAMTS7 Protein
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Animals
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Aorta, Abdominal / enzymology
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Aorta, Abdominal / pathology
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Aortic Diseases / chemically induced
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Aortic Diseases / enzymology*
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Aortic Diseases / genetics
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Aortic Diseases / pathology
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Calcium Chloride
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Carotid Artery Diseases / chemically induced
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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, Common / enzymology
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Carotid Artery, Common / pathology
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Cartilage Oligomeric Matrix Protein
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Cells, Cultured
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Computational Biology
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Disease Models, Animal
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Down-Regulation
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Extracellular Matrix Proteins / metabolism
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Female
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Gene Expression Regulation, Enzymologic
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Glycoproteins / metabolism
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Humans
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Kidney Failure, Chronic / complications
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Kidney Failure, Chronic / enzymology
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Kidney Failure, Chronic / genetics
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Matrilin Proteins
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MicroRNAs / metabolism*
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Muscle, Smooth, Vascular / enzymology*
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Muscle, Smooth, Vascular / pathology
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Myocytes, Smooth Muscle / enzymology*
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Myocytes, Smooth Muscle / pathology
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Nephrectomy
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Organ Culture Techniques
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Promoter Regions, Genetic
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RNA Interference
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Rats
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Rats, Sprague-Dawley
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Real-Time Polymerase Chain Reaction
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Time Factors
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Transcription, Genetic
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Transfection
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Up-Regulation
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Uremia / enzymology
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Uremia / pathology
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Vascular Calcification / chemically induced
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Vascular Calcification / enzymology*
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Vascular Calcification / genetics
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Vascular Calcification / pathology
Substances
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3' Untranslated Regions
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Cartilage Oligomeric Matrix Protein
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Extracellular Matrix Proteins
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Glycoproteins
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MIRN29 microRNA, rat
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Matrilin Proteins
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MicroRNAs
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TSP5 protein, human
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ADAM Proteins
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ADAMTS7 Protein
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ADAMTS7 protein, human
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Adamts7 protein, rat
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Calcium Chloride