Vascular calcification (VC) is an independent risk factor for cardiovascular events and all-cause mortality with the absence of current treatment. This study aimed to investigate whether eIF2alpha phosphorylation inhibition could ameliorate VC. VC in rats was induced by administration of vitamin D3 (3×10(5) IU/kg, intramuscularly) plus nicotine (25 mg/kg, intragastrically). ISRIB (0.25 mg/kg·week), an inhibitor of eIF2alpha phosphorylation, ameliorated the elevation of calcium deposition and ALP activity in calcified rat aortas, accompanied by amelioration of increased SBP, PP, and PWV. The decreased protein levels of calponin and SM22alpha, and the increased levels of RUNX2 and BMP2 in calcified aorta were all rescued by ISRIB, while the increased levels of the GRP78, GRP94, and C/EBP homologous proteins in rats with VC were also attenuated. Moreover, ISRIB could prevent the elevation of eIF2alpha phosphorylation and ATF4, and partially inhibit PERK phosphorylation in the calcified aorta. These results suggested that an eIF2alpha phosphorylation inhibitor could ameliorate VC pathogenesis by blocking eIF2alpha/ATF4 signaling, which may provide a new target for VC prevention and treatment.

• MeSH
• aorta metabolismus   MeSH
• cholekalciferol metabolismus   MeSH
• eukaryotický iniciační faktor 2 * MeSH
• fosforylace MeSH
• krysa rodu Rattus MeSH
• vaskulární kalcifikace * chemicky indukované   farmakoterapie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholekalciferol MeSH
• eukaryotický iniciační faktor 2 * MeSH

Circulating levels of soluble receptor for advanced glycation end-products (sRAGE) have been suggested to have a protective role in neutralizing advanced glycation end-products (AGEs) and their pathological effects on vessel walls. We aimed to investigate the association between the circulating concentration of sRAGE and the dynamics of arterial wall stiffening as a manifestation of vascular aging in the general population. In a prospective cohort study, we longitudinally followed 530 general-population-based subjects (subsample of Czech post-MONICA study). Aortic pulse wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE were assessed at baseline by ELISA (R&D Systems). The average ∆PWV/year significantly decreased across the sRAGE quintiles (p = 0.048), and a drop by one sRAGE quintile was associated with an ~21% increase in the relative risk of accelerated age-dependent stiffening (∆PWV/year ≥ 0.2 m/s). Subjects in the bottom quintile of sRAGE (<889.74 pg/mL) had a fully adjusted odds ratio of accelerated stiffening of 1.72 (95% CI: 1.06-2.79), p = 0.028, while those with high sRAGE concentrations (≥1695.2 pg/mL) showed the opposite effect [odds ratio 0.55 (95% CI: 0.33-0.90), p = 0.017]. In conclusion, the circulating status of sRAGE independently influenced the individual progression of arterial stiffness over time. This finding strongly supports the hypothesis that high sRAGE has a protective role against vascular aging.

• Klíčová slova
• AGEs, General population, Prospective study, Pulse wave velocity, Vascular aging, sRAGE,
• MeSH
• analýza pulzové vlny MeSH
• dospělí MeSH
• krevní tlak fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• prospektivní studie MeSH
• receptor pro konečné produkty pokročilé glykace krev   MeSH
• senioři MeSH
• stárnutí metabolismus   MeSH
• tuhost cévní stěny fyziologie   MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• receptor pro konečné produkty pokročilé glykace MeSH

Matrix Gla protein (MGP), a natural inhibitor of calcification, strongly correlates with the extent of coronary calcification. Vitamin K is the essential cofactor for the activation of MGP. The nonphosphorylated-uncarboxylated isoform of MGP (dp-ucMGP) reflects the status of this vitamin. We investigated whether there is an association between dp-ucMGP and stiffness of elastic and muscular-type large arteries in a random sample from the general population. In a cross-sectional design, we analyzed 1087 subjects from the Czech post-MONICA study. Aortic and femoro-popliteal pulse wave velocities (PWVs) were measured using a Sphygmocor device. Dp-ucMGP concentrations were assessed in freshly frozen samples by enzyme-linked immunosorbent assay methods using the InaKtif MGP iSYS pre-commercial kit developed by IDS and VitaK. Aortic PWV significantly (P<0.0001) increased across the dp-ucMGP quartiles. After adjustment for all potential confounders, aortic PWV independently correlated with dp-ucMGP (with beta coefficient (s.d.) 11.61 (5.38) and P-value=0.031). In a categorized manner, subjects in the top quartile of dp-ucMGP (⩾ 671 pmol l(-1)) had a higher risk of elevated aortic PWV, with corresponding adjusted odds ratio (95% confidence interval) 1.73 (1.17-2.5). In contrast, no relation between dp-ucMGP and femoro-popliteal PWV was found. In conclusion, increased dp-ucMGP, which is a circulating biomarker of vitamin K status and vascular calcification, is independently associated with aortic stiffness, but not with stiffness of distal muscular-type arteries.

• MeSH
• analýza pulzové vlny MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• ELISA MeSH
• extracelulární matrix - proteiny krev   MeSH
• fosforylace MeSH
• lidé středního věku MeSH
• lidé MeSH
• lineární modely MeSH
• logistické modely MeSH
• matrixový protein Gla MeSH
• multivariační analýza MeSH
• nemoci aorty krev   diagnóza   patofyziologie   MeSH
• odds ratio MeSH
• onemocnění periferních arterií krev   diagnóza   patofyziologie   MeSH
• proteiny vázající vápník krev   MeSH
• průřezové studie MeSH
• rizikové faktory MeSH
• senioři MeSH
• tuhost cévní stěny * MeSH
• upregulace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• biologické markery MeSH
• extracelulární matrix - proteiny MeSH
• proteiny vázající vápník MeSH