Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system.

OBJECTIVE: Vascular and valvular calcifications are pathological processes regulated by resident cells, and depending on a complex interplay between calcification promoters and inhibitors, resembling skeletal metabolism. Here, we study the role of the vitamin K-dependent Gla-rich protein (GRP) in vascular and valvular calcification processes. APPROACH AND RESULTS: Immunohistochemistry and quantitative polymerase chain reaction showed that GRP expression and accumulation are upregulated with calcification simultaneously with osteocalcin and matrix Gla protein (MGP). Using conformation-specific antibodies, both γ-carboxylated GRP and undercarboxylated GRP species were found accumulated at the sites of mineral deposits, whereas undercarboxylated GRP was predominant in calcified aortic valve disease valvular interstitial cells. Mineral-bound GRP, MGP, and fetuin-A were identified by mass spectrometry. Using an ex vivo model of vascular calcification, γ-carboxylated GRP but not undercarboxylated GRP was shown to inhibit calcification and osteochondrogenic differentiation through α-smooth muscle actin upregulation and osteopontin downregulation. Immunoprecipitation assays showed that GRP is part of an MGP-fetuin-A complex at the sites of valvular calcification. Moreover, extracellular vesicles released from normal vascular smooth muscle cells are loaded with GRP, MGP, and fetuin-A, whereas under calcifying conditions, released extracellular vesicles show increased calcium loading and GRP and MGP depletion. CONCLUSIONS: GRP is an inhibitor of vascular and valvular calcification involved in calcium homeostasis. Its function might be associated with prevention of calcium-induced signaling pathways and direct mineral binding to inhibit crystal formation/maturation. Our data show that GRP is a new player in mineralization competence of extracellular vesicles possibly associated with the fetuin-A-MGP calcification inhibitory system. GRP activity was found to be dependent on its γ-carboxylation status, with potential clinical relevance.

Third version of vendor-specific model-based iterativereconstruction (Veo 3.0): evaluation of CT image quality in the abdomen using new noise reduction presets and varied slice optimization.

OBJECTIVE: To qualitatively and quantitatively compare abdominal CT images reconstructed with a newversion of model-based iterative reconstruction (Veo 3.0; GE Healthcare Waukesha, WI) utilizing varied presetsof resolution preference, noise reduction and slice optimization. METHODS: This retrospective study was approved by our Institutional Review Board and was Health Insurance Portability and Accountability Act compliant. The raw datafrom 30 consecutive patients who had undergone CT abdomen scanning were used to reconstructfour clinical presets of 3.75mm axial images using Veo 3.0: 5% resolution preference (RP05n), 5%noise reduction (NR05) and 40% noise reduction (NR40) with new 3.75mm "sliceoptimization," as well as one set using RP05 with conventional 0.625mm "slice optimization" (RP05c). The images were reviewed by two independent readers in a blinded, randomized manner using a 5-point Likert scale as well as a 5-point comparative scale. Multiple two-dimensional circular regions of interest were defined for noise and contrast-to-noise ratio measurements. Line profiles were drawn across the 7 lp cm-1 bar pattern of the Catphan 600 phantom for evaluation of spatial resolution. RESULTS: The NR05 image set was ranked as the best series in overall image quality (mean difference inrank 0.48, 95% CI [0.081-0.88], p = 0.01) and with specific reference to liver evaluation (meandifference 0.46, 95% CI [0.030-0.89], p = 0.03), when compared with the secondbest series ineach category. RP05n was ranked as the best for bone evaluation. NR40 was ranked assignificantly inferior across all assessed categories. Although the NR05 and RP05c image setshad nearly the same contrast-to-noise ratio and spatial resolution, NR05 was generally preferred. Image noise and spatial resolution increased along a spectrum with RP05n the highest and NR40the lowest. Compared to RP05n, the average noise was 21.01% lower for NR05, 26.88%lower for RP05c and 50.86% lower for NR40. CONCLUSION: Veo 3.0 clinical presets allow for selection of image noise and spatial resolution balance; for contrast-enhanced CT evaluation of the abdomen, the 5% noise reduction preset with 3.75 mm slice optimization (NR05) was generally ranked superior qualitatively and, relative to other series, was in the middle of the spectrum with reference to image noise and spatial resolution. Advances in knowledge: To our knowledge, this is the first study of Veo 3.0 noise reduction presets and varied slice optimization. This study provides insight into the behaviour of slice optimization and documents the degree of noise reduction and spatial resolution changes that users can expect across various Veo 3.0 clinical presets. These results provide important parameters to guide preset selection for both clinical and research purposes.

Gla-rich protein is a potential new vitamin K target in cancer: evidences for a direct GRP-mineral interaction.

Gla-rich protein (GRP) was described in sturgeon as a new vitamin-K-dependent protein (VKDP) with a high density of Gla residues and associated with ectopic calcifications in humans. Although VKDPs function has been related with γ-carboxylation, the Gla status of GRP in humans is still unknown. Here, we investigated the expression of recently identified GRP spliced transcripts, the γ-carboxylation status, and its association with ectopic calcifications, in skin basal cell and breast carcinomas. GRP-F1 was identified as the predominant splice variant expressed in healthy and cancer tissues. Patterns of γ-carboxylated GRP (cGRP)/undercarboxylated GRP (ucGRP) accumulation in healthy and cancer tissues were determined by immunohistochemistry, using newly developed conformation-specific antibodies. Both GRP protein forms were found colocalized in healthy tissues, while ucGRP was the predominant form associated with tumor cells. Both cGRP and ucGRP found at sites of microcalcifications were shown to have in vitro calcium mineral-binding capacity. The decreased levels of cGRP and predominance of ucGRP in tumor cells suggest that GRP may represent a new target for the anticancer potential of vitamin K. Also, the direct interaction of cGRP and ucGRP with BCP crystals provides a possible mechanism explaining GRP association with pathological mineralization.