Protein carbamylation exacerbates vascular calcification

Mori, Daisuke; Matsui, Isao; Shimomura, Atsushi; Hashimoto, Nozomi; Matsumoto, Ayumi; Shimada, Kazuaki; Yamaguchi, Satoshi; Oka, Tetsushi; Kubota, Keiichi; Yonemoto, Sayoko; Sakaguchi, Yusuke; Takahashi, Atsushi; Shintani, Yasunori; Takashima, Seiji; Takabatake, Yoshitsugu; Hamano, Takayuki; Isaka, Yoshitaka

doi:10.1016/j.kint.2018.01.033

Cited by 55 publications

(62 citation statements)

References 55 publications

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“…In clinical perspective, the mechanism by which high urea contributes to VC was recently revealed. High urea, as observed in CKD, causes a posttranslational modification known as carbamylation [289]. Intriguingly, mitochondrial proteins, including ATP synthase, are also carbamylated, deteriorating their own function, thereby inducing oxidative stress and mitochondrial dysfunction [289].…”

Section: Mitochondrial Dysfunction and Defective Mitophagy In Vascumentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

255

254

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Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

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Section: Mitochondrial Dysfunction and Defective Mitophagy In Vascumentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

255

254

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“…26 Furthermore, cyanates could react with, and covalently bind to, glutathione which is a major lung antioxidant that plays an important role for reducing oxidative stress and airway inflammation. 29 The reason as to why albumin was used as a model protein to study carbamylation was because it was easily available and that it, although to a small extent, also could be found in the lung where it could act as an antioxidant. 27 Studies in a mice model of allergic asthma have also shown that depletion of glutathione will result in an exacerbated allergic asthma.…”

Section: Concentration Of Ica Mic and Hcn In Frying Fumes (μG/m 3 ) Bmentioning

confidence: 99%

“…28 It has recently also been found that carbamylation exacerbates vascular calcification by inactivation of an enzyme that plays a key role for the inhibition of this and that it thereby could play a role in vascular pathology. 29 The reason as to why albumin was used as a model protein to study carbamylation was because it was easily available and that it, although to a small extent, also could be found in the lung where it could act as an antioxidant. 30 Others have also shown that albumin, and also high-and low-density lipoproteins, can be carbamylated and that this could impair their normal function.…”

Section: Concentration Of Ica Mic and Hcn In Frying Fumes (μG/m 3 ) Bmentioning

confidence: 99%

Isocyanates and hydrogen cyanide in fumes from heated proteins and protein‐rich foods

Leanderson

2018

Indoor Air

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Toxic compounds in cooking fumes could cause respiratory problems. In the present study, the formation of isocyanic acid (ICA), methyl isocyanate (MIC), and hydrogen cyanide (HCN) was studied during the heating of proteins or frying of protein‐rich foods. Heating was performed in an experimental setup using a tube oven set at 200‐500°C and in a kitchen when foods with different protein content were fried at a temperature around 300°C. ICA, MIC, and HCN were all generated when protein or meat was heated. Individual amino acids were also heated, and there was a significant positive correlation between their respective nitrogen content and the formation of the measured compounds. Gas from heated protein or meat also caused carbamylation in albumin. ICA, MIC, and HCN were also present in fumes generated when meat, egg, and halloumi were fried in a kitchen pan. The levels of ICA were here twice that of the Swedish occupational exposure limit. If ICA, MIC, and HCN in fumes from heated protein‐rich foods could contribute to the risk of airway dysfunction among those exposed is not clear, but it is important to avoid inhaling frying and grilling fumes and to equip kitchens with good exhaust ventilation.

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“…We reported preclinical data that protein carbamylation exacerbated the calcification of human vascular smooth muscle cells by suppressing the expression of ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1), a key enzyme in the generation of pyrophosphate, a potent inhibitor of ectopic calcification. This finding was confirmed using ex vivo and in vivo models with medial vascular calcification . On the basis of these data, keeping the time‐averaged concentration of serum urea as low as possible may help prevent progression of vascular calcification.…”

Section: Potential Solutions For Vascular Calcification In the Futurementioning

confidence: 99%

“…This finding was confirmed using ex vivo and in vivo models with medial vascular calcification. 35 On the basis of these data, keeping the time-averaged concentration of serum urea as low as possible may help prevent progression of vascular calcification. Whether adequate dialysis dose is protective against ectopic calcification in humans independent of serum phosphate levels requires further study.…”

Section: Adequate Dialysismentioning

confidence: 99%

Mineral and bone disorders in conventional hemodialysis: Challenges and solutions

Hamano

2018

Seminars in Dialysis

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Despite the advent of cinacalcet and noncalcium-containing phosphate binders, controlling the progression of vascular calcification (VC) is still challenging. Recent reports demonstrate that carbamylation driven by high urea concentration aggravates VC, suggesting the importance of adequate dialysis in retarding its progression. Theoretically, other promising measures include the use of iron-based phosphate binders, vitamin K, and magnesium supplements, which should be investigated in future randomized controlled trials (RCTs), ideally with hard outcomes. While incidence of hip fracture in patients on dialysis is decreasing in the United States and Japan (possibly owing to better control of PTH levels by cinacalcet) it remains much higher than that in the general population. Many drugs used in the treatment of osteoporosis, including bisphosphonate, raloxifene, denosumab, and teriparatide can, under specific conditions, increase bone mineral density (BMD), which is associated with a lower fracture rate. However, the efficacy of these drugs in reducing the fracture rate remains to be proven in hemodialysis (HD) patients, given their adverse effects such as severe hypocalcemia and resultant worsening of secondary hyperparathyroidism. Some clinical studies have shown that cinacalcet, lanthanum carbonate, and sevelamer reduce mortality in elderly patients on HD, suggesting the benefits of reducing PTH and serum phosphate levels. However, the target ranges of PTH and phosphate levels are based solely on observational studies. This is also the case when treating low PTH levels by decreasing vitamin D or calcium load. RCTs with hard clinical endpoints comparing different targets are necessary in the future.

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Protein carbamylation exacerbates vascular calcification

Cited by 55 publications

References 55 publications

Vascular Calcification—New Insights into Its Mechanism

Vascular Calcification—New Insights into Its Mechanism

Isocyanates and hydrogen cyanide in fumes from heated proteins and protein‐rich foods

Mineral and bone disorders in conventional hemodialysis: Challenges and solutions

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