Protein carbamylation exacerbates vascular calcification
Autor: | Isao Matsui, Satoshi Yamaguchi, Takayuki Hamano, Karin Shimada, Yasunori Shintani, Keiichi Kubota, Nobuhiro Hashimoto, Yoshitaka Isaka, Yoshitsugu Takabatake, Sayoko Yonemoto, Akihiro Shimomura, Atsushi Takahashi, Seiji Takashima, Yusuke Sakaguchi, Daisuke Mori, Tatsufumi Oka, Ayumi Matsumoto |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Male medicine.medical_specialty Vascular smooth muscle 030204 cardiovascular system & hematology medicine.disease_cause Pyrophosphate Muscle Smooth Vascular Cell Line Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Ectopic calcification 0302 clinical medicine Internal medicine medicine Animals Humans Pyrophosphatases Vascular Calcification Uremia Membrane Potential Mitochondrial Gene knockdown Protein Carbamylation Chemistry Superoxide Phosphoric Diester Hydrolases Phosphodiesterase medicine.disease Rats Disease Models Animal Oxidative Stress 030104 developmental biology Endocrinology Nephrology Gene Knockdown Techniques Disease Progression Kidney Failure Chronic Oxidative stress Calcification |
Zdroj: | Kidney international. 94(1) |
ISSN: | 1523-1755 |
Popis: | Protein carbamylation is a posttranslational modification that can occur non-enzymatically in the presence of high concentrations of urea. Although carbamylation is recognized as a prognostic biomarker, the contribution of protein carbamylation to organ dysfunction remains uncertain. Because vascular calcification is common under carbamylation-prone situations, we investigated the effects of carbamylation on this pathologic condition. Protein carbamylation exacerbated the calcification of human vascular smooth muscle cells (hVSMCs) by suppressing the expression of ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1), a key enzyme in the generation of pyrophosphate, which is a potent inhibitor of ectopic calcification. Several mitochondrial proteins were carbamylated, although ENPP1 itself was not identified as a carbamylated protein. Rather, protein carbamylation reduced mitochondrial membrane potential and exaggerated mitochondria-derived oxidative stress, which down-regulated ENPP1. The effects of carbamylation on ectopic calcification were abolished in hVSMCs by ENPP1 knockdown, in mitochondrial-DNA-depleted hVSMCs, and in hVSMCs treated with a mitochondria-targeted superoxide scavenger. We also evaluated the carbamylation effects using ex vivo and in vivo models. The tunica media of a patient with end-stage renal disease was carbamylated. Thus, our findings have uncovered a previously unrecognized aspect of uremia-related vascular pathology. |
Databáze: | OpenAIRE |
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