Ucma/GRP inhibits phosphate-induced vascular smooth muscle cell calcification via SMAD-dependent BMP signalling

Vascular calcification (VC) is the process of deposition of calcium phosphate crystals in the blood vessel wall, with a central role for vascular smooth muscle cells (VSMCs). VC is highly prevalent in chronic kidney disease (CKD) patients and thought, in part, to be induced by phosphate imbalance. The molecular mechanisms that regulate VC are not fully known. Here we propose a novel role for the mineralisation regulator Ucma/GRP (Upper zone of growth plate and Cartilage Matrix Associated protein/Gla Rich Protein) in phosphate-induced VSMC calcification. We show that Ucma/GRP is present in calcified atherosclerotic plaques and highly expressed in calcifying VSMCs in vitro. VSMCs from Ucma/GRP(-/-) mice showed increased mineralisation and expression of osteo/chondrogenic markers (BMP-2, Runx2, beta-catenin, p-SMAD1/5/8, ALP, OCN), and decreased expression of mineralisation inhibitor MGP, suggesting that Ucma/GRP is an inhibitor of mineralisation. Using BMP signalling inhibitor noggin and SMAD1/5/8 signalling inhibitor dorsomorphin we showed that Ucma/GRP is involved in inhibiting the BMP-2-SMAD1/5/8 osteo/chondrogenic signalling pathway in VSMCs treated with elevated phosphate concentrations. Additionally, we showed for the first time evidence of a direct interaction between Ucma/GRP and BMP-2. These results demonstrate an important role of Ucma/GRP in regulating osteo/chondrogenic differentiation and phosphate-induced mineralisation of VSMCs.NWO ZonMw [MKMD 40-42600-98-13007]; FCT [SFRH/BPD/70277/2010]info:eu-repo/semantics/publishedVersio

Use of Chronic Kidney Disease to Enhance Prediction of Cardiovascular Risk in Those at Medium Risk

Based on global cardiovascular (CV) risk assessment for example using the Framingham risk score, it is recommended that those with high risk should be treated and those with low risk should not be treated. The recommendation for those of medium risk is less clear and uncertain. We aimed to determine whether factoring in chronic kidney disease (CKD) will improve CV risk prediction in those with medium risk. This is a 10-year retrospective cohort study of 905 subjects in a primary care clinic setting. Baseline CV risk profile and serum creatinine in 1998 were captured from patients record. Framingham general cardiovascular disease risk score (FRS) for each patient was computed. All cardiovascular disease (CVD) events from 1998-2007 were captured. Overall, patients with CKD had higher FRS risk score (25.9% vs 20%, p = 0.001) and more CVD events (22.3% vs 11.9%, p = 0.002) over a 10-year period compared to patients without CKD. In patients with medium CV risk, there was no significant difference in the FRS score among those with and without CKD (14.4% vs 14.6%, p = 0.84) However, in this same medium risk group, patients with CKD had more CV events compared to those without CKD (26.7% vs 6.6%, p = 0.005). This is in contrast to patients in the low and high risk group where there was no difference in CVD events whether these patients had or did not have CKD. There were more CV events in the Framingham medium risk group when they also had CKD compared those in the same risk group without CKD. Hence factoring in CKD for those with medium risk helps to further stratify and identify those who are actually at greater risk, when treatment may be more likely to be indicated