Impacts of Febuxostat on Cerebral and Cardiovascular Events in Elderly Patients with Hyperuricemia: Post Hoc Analysis of a Randomized Controlled Trial.

A recent meta-analysis found no benefit of uric acid-lowering therapy including febuxostat on death, cardiovascular events, or renal impairment. However, there may be populations that benefit from febuxostat in reducing mortality and cerebral and cardiovascular events. The aim of the present study was to examine the clinical benefit of febuxostat in elderly patients stratified by age using Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED) data. FREED was a randomized study involving patients aged 65 years or older with hyperuricemia and risk factors for cerebral, cardiovascular, or renal diseases. A total of 1,070 patients were included in this post hoc analysis, divided into 2 age groups: 65-74 years and ≥ 75 years. Patients were randomized into febuxostat and non-febuxostat groups, with uric acid levels monitored for 36 months. The primary composite end point included cerebral, cardiovascular, and renal events. In patients aged between 65 and 74 years, febuxostat significantly reduced the risk of future cerebral and cardiorenovascular events. However, no effects of febuxostat were found in the older population aged ≥ 75 years. Heterogeneity in potential interactions between the age and febuxostat treatment was particularly observed in non-fatal cerebral and cardiovascular events and all-cause death. Patients aged ≥ 75 years exhibited more pre-existing factors associated with cerebral and cardiorenovascular events than those aged 65-74 years. The effectiveness of febuxostat varies by age group, with potential benefits for patients aged 65-74 years. The effects of febuxostat are complex and it is important to consider patient characteristics in its clinical use.

Proteotoxic stresses stimulate dissociation of UBL4A from the tail-anchored protein recognition complex.

Inclusion body formation is associated with cytotoxicity in a number of neurodegenerative diseases. However, the molecular basis of the toxicity caused by the accumulation of aggregation-prone proteins remains controversial. In this study, we found that disease-associated inclusions induced by elongated polyglutamine chains disrupt the complex formation of BAG6 with UBL4A, a mammalian homologue of yeast Get5. UBL4A also dissociated from BAG6 in response to proteotoxic stresses such as proteasomal inhibition and mitochondrial depolarization. These findings imply that the cytotoxicity of pathological protein aggregates might be attributed in part to disruption of the BAG6-UBL4A complex that is required for the biogenesis of tail-anchored proteins.

Protein quality control machinery supports primary ciliogenesis by eliminating GDP-bound Rab8-family GTPases.

The small GTPase Rab8 plays a vital role in the vesicular trafficking of cargo proteins from the trans-Golgi network to target membranes. Upon reaching its target destination, Rab8 is released from the vesicular membrane into the cytoplasm via guanosine triphosphate (GTP) hydrolysis. The fate of GDP-bound Rab8 released from the destination membranes, however, has not been investigated adequately. In this study, we found that GDP-bound Rab8 subfamily proteins are targeted for immediate degradation, and the pre-emptive quality control machinery is responsible for eliminating these proteins in a nucleotide-specific manner. We provide evidence that components of this quality control machinery have a critical role in vesicular trafficking events, including the formation of primary cilia, a process regulated by the Rab8 subfamily. These results suggest that the protein degradation machinery plays a critical role in the integrity of membrane trafficking by limiting the excessive accumulation of GDP-bound Rab8 subfamily proteins.

Febuxostat and renal outcomes: post-hoc analysis of a randomized trial.

Effect of urate-lowering on renal outcomes in patients at high-risk for cardiovascular disease with hyperuricemia without gout is not known. We conducted a post hoc analysis of a randomized trial (Febuxostat for Cerebral and　CaRdiorenovascular Events PrEvEntion StuDy [FREED]). The FREED trial enrolled 1070 asymptomatic, hyperuricemic elderly patients with at least one risk factor for cardiovascular disease, divided into febuxostat (n = 537) and non-febuxostat (n = 533) groups. We compared the effect of these treatments on renal outcomes including 40% decline in estimated glomerular filtration rate, new onset of microalbuminuria and development or worsening macroalbuminuria. The relative risk of developing or worsening macroalbuminuria was 56% lower in the febuxostat group (hazard ratio, 0.44; 95% CI, 0.24-0.82; P = 0.0098). However, the risks for other outcomes were comparable. In patients with asymptomatic hyperuricemia without gout, febuxostat reduces the risk of development or worsening of macroalbuminuria.

C-reactive Protein Levels and Cardiovascular Outcomes After Febuxostat Treatment in Patients with Asymptomatic Hyperuricemia: Post-hoc Analysis of a Randomized Controlled Study.

PURPOSE: Inflammation plays an important role in the initiation and progression of atherosclerosis, leading to poor clinical outcomes. Hyperuricemia is associated with the activation of the Nod-like receptor protein 3 inflammasome. Here, we investigated whether inhibition of inflammation using febuxostat lowered the risk of cardiovascular events. METHODS: This is a post-hoc analysis of the randomized trial, Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED). In total, 1067 patients (736 men and 331 women) were included in the analysis. We compared the serial changes in high-sensitivity C-reactive protein (hs-CRP) levels between febuxostat and non-febuxostat groups and assessed the correlation between the changes in uric acid (UA) and hs-CRP levels after febuxostat treatment. We also determined whether febuxostat could reduce a hard endpoint, defined as a composite of cardiovascular events and all-cause mortality. RESULTS: Serum UA levels in the febuxostat group were significantly lower than those in the non-febuxostat group after randomization (p < 0.05). However, hs-CRP levels were comparable between the two groups during the study. No significant correlation was observed between the changes in UA and hs-CRP levels after febuxostat treatment. The hard endpoints did not differ significantly between the two groups. In patients with baseline hs-CRP levels > 0.2 mg/dL or those administered 40 mg of febuxostat, the drug did not reduce hs-CRP levels or decrease the hard endpoint. CONCLUSION: Febuxostat reduced the UA levels but did not affect the CRP levels, and therefore may fail to improve cardiovascular outcomes after treatment. TRIAL REGISTRATION: ClinicalTrial.gov (NCT01984749). https://clinicaltrials.gov/ct2/show/NCT01984749.

Impact of febuxostat on visit-to-visit blood pressure variability: insights from the randomised PRIZE Study.

OBJECTIVES: Although uric acid lowering therapies, including xanthine oxidase (XO) inhibition, may reduce the absolute level of blood pressure (BP), the effect of XO inhibition on BP variability is largely unknown. The aim of the present analysis was to evaluate the impact of febuxostat, an XO inhibitor, on BP variability in a randomised trial setting. METHODS: This was a subanalysis of the PRIZE Study, a randomised trial to evaluate the potential effect of febuxostat on carotid intima-media thickness progression. Patients with hyperuricemia and carotid plaques were randomly assigned to the febuxostat or control group. During a 24-month period, office BP and pulse rate (PR) were measured ≥3 times. BP and PR variabilities were assessed with SD and coefficient of variation (CV). The effect of febuxostat on BP and PR variabilities was adjusted with age, sex and baseline BP or PR, expressed with 95% CIs. RESULTS: A total of 472 patients were included into the present subanalysis. During the 24-month follow-up period, the febuxostat group had a significantly lower adjusted mean systolic BP (128.4 (126.8-130.0) vs 130.7 (129.1-132.2) mm Hg, p=0.04) and CV of systolic BP (7.4 (6.7-8.0) vs 8.2 (7.6-8.8), p=0.04) than the control group. Adjusted SD of PR was also lower in the febuxostat group than their counterpart (5.95 (4.93-6.97) vs 7.33 (6.32-8.33), p=0.04). CONCLUSION: XO inhibition with febuxostat was associated with reduced visit-to-visit BP variability as well as reduced PR variability in patients with hyperuricemia and carotid plaques. TRIAL REGISTRATION NUMBERS: University Hospital Medical Information Network Clinical Trial Registry (UMIN000012911 and UMIN000041322).

Optimal uric acid levels by febuxostat treatment and cerebral, cardiorenovascular risks: post hoc analysis of a randomized controlled trial.

OBJECTIVES: Hyperuricaemia is recognized as an independent risk marker for cardiovascular and renal diseases. However, uric acid is a powerful free-radical scavenger, and the optimal level of serum uric acid (SUA) determining outcomes is unknown. This study explored whether interventional treatments for excessive SUA reduction were harmful and what constituted the optimal lowering of SUA levels for the prevention of events in patients with asymptomatic hyperuricaemia. METHODS: This was a post hoc analysis of a randomized trial (Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy [FREED]) in which 1070 older patients with asymptomatic hyperuricaemia were enrolled and allocated to febuxostat (n = 537) or non-febuxostat treatment group (n = 533). We assessed the relationship between the endpoint (withdrawal or study completion) SUA levels and clinical outcomes. Primary endpoint was defined as a composite of all-cause mortality, cerebral and cardiorenovascular events. RESULTS: In the febuxostat group, patients achieving SUA levels ≤4 mg/dl (hazard ratio: 2.01 [95% CI: 1.05, 3.87]), >4 to ≤5 mg/dl (2.12 [1.07, 4.20], >6 to ≤7 mg/dl (2.42 [1.05, 5.60]), and >7 mg/dl (4.73 [2.13, 10.5]) had significantly higher risks for a primary composite event than those achieving SUA levels >5 to ≤6 mg/dl (P = 0.003 [log-rank test]). This J-shaped relationship applied to patients with renal impairment (P = 0.007 [Gray's test]) and was not significant in the non-febuxostat treatment group (P = 0.212 [log-rank test]). CONCLUSION: Optimal SUA level by febuxostat treatment is 5-6 mg/dl for reducing all-cause mortality, cerebral, cardiovascular and renal events. Excessive SUA reduction may be harmful in older hyperuricaemic populations. TRIAL REGISTRATION: ClinicalTrial.gov, https://clinicaltrials.gov, NCT01984749.

Effect of febuxostat on clinical outcomes in patients with hyperuricemia and cardiovascular disease.

BACKGROUND: We previously reported on the FREED study, which found that febuxostat reduced the risk of adverse clinical outcome in patients with asymptomatic hyperuricemia without gout. We have now investigated outcomes in subgroups of FREED patients with and without a history of cardiovascular disease (CVD). METHODS: We performed a post hoc subgroup analysis of 1070 patients randomized to the febuxostat or non-febuxostat group and followed for 36 months. RESULTS: At baseline, 234 patients (21.9%) had a history of CVD, including 86 patients with stroke (36.8%), 90 with coronary artery disease (38.5%), 74 with heart failure (31.6%), and 25 with vascular disease (10.7%). The risk for the primary composite endpoint, i.e., cerebral, cardiovascular, and renal events and all deaths, was higher in patients with CVD than in those without CVD (34.2% vs 23.7%; p < 0.001). Treatment with febuxostat lowered rates of the primary composite endpoint in patients with CVD (hazard ratio [HR] 0.601, 95% CI 0.384 to 0.940, p = 0.026), and these effects were consistently observed in subgroups with and without CVD (p = 0.227 for treatment by subgroup interaction). Furthermore, in the subgroup with CVD, all-cause mortality was significantly lower in the febuxostat group than in the non-febuxostat group (HR 0.160, 95% CI 0.047 to 0.547, p = 0.004), with a significant subgroup interaction (p = 0.007 for treatment by subgroup interaction). CONCLUSIONS: In patients with asymptomatic hyperuricemia without gout, febuxostat reduces the risk of the composite of cerebral, cardiovascular, and renal events and death in the secondary prevention setting.

Nuclear accumulation of ZFP36L1 is cell cycle-dependent and determined by a C-terminal serine-rich cluster.

ZFP36L1 is an RNA-binding protein responsible for mRNA decay in the cytoplasm. ZFP36L1 has also been suggested as a nuclear-cytoplasmic shuttling protein because it contains a potential nuclear localization signal and a nuclear export signal. However, it remains unclear how the nuclear localization of ZFP36L1 is controlled. In this study, we provide evidence that the nuclear accumulation of ZFP36L1 protein is modulated in a cell cycle-dependent manner. ZFP36L1 protein accumulation in fractionated nuclei was particularly prominent in cells arrested at G1-/S-phase boundary, while it was downregulated in S-phase cells, and eventually disappeared in G2-phase nuclei. Moreover, forced nuclear targeting of ZFP36L1 revealed marked downregulation of this protein in S- and G2-phase cells, suggesting that ZFP36L1 can be eliminated in the nucleus. The C-terminal serine-rich cluster of ZFP36L1 is critical for the regulation of its nuclear accumulation because truncation of this probable disordered region enhanced the nuclear localization of ZFP36L1, increased its stability and abolished its cell cycle-dependent fluctuations. These findings provide the first hints to the question of how ZFP36L1 nuclear accumulation is controlled during the course of the cell cycle.

BAG6 contributes to glucose uptake by supporting the cell surface translocation of the glucose transporter GLUT4.

Defective translocation of glucose transporter 4 (GLUT4) to the cell surface is a key feature of insulin resistance in type 2 diabetes. Therefore, elucidating the mechanism of GLUT4 translocation is of primary importance. The mammalian Bag6/Bat3 gene has been suggested to be linked with potential obesity- and diabetes-associated loci, while its function in the control of glucose incorporation into the cytoplasm has not been investigated. In this study, we established a series of cell lines that stably expressed GLUT4 with three tandem repeats of the antigenic peptide inserted into its 1st extracellular loop. With these cell lines, we found that the depletion of endogenous BAG6 downregulated the cell surface expression of GLUT4, concomitant with the reduced incorporation of a glucose analog into the cells. Defective intracellular translocation of GLUT4 in BAG6-depleted cells is similar to the case observed for the depletion of Rab8a, an essential regulator of insulin-stimulated GLUT4 translocation. In addition, we observed that the assembly of syntaxin 6 into the endoplasmic reticulum membrane was slightly disturbed under BAG6 depletion. Given that Rab8a and syntaxin 6 are critical for GLUT4 translocation, we suggest that BAG6 may play multiple roles in the trafficking of glucose transporters to the cell surface.This article has an associated First Person interview with the first author of the paper.

Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.

BACKGROUND: Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. METHODS: This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. RESULTS: Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. CONCLUSIONS: LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.

BAG6 deficiency induces mis-distribution of mitochondrial clusters under depolarization.

Accumulation of damaged mitochondria is implicated in a number of neurodegenerative disorders, including Parkinson's disease. Therefore, the machinery for mitochondrial quality control is important for the prevention of such diseases. It has been reported that Parkin- and p62/sequestosome 1 (SQSTM1)-mediated clustering and subsequent elimination of damaged mitochondria (termed mitophagy) are critical for maintaining the quality of mitochondria under stress induced by uncoupling agents such as carbonyl cyanide m-chlorophenyl hydrazone. However, the molecular mechanisms underlying mitochondrial translocation to the perinuclear region during mitophagy have not been adequately addressed to date. In this study, we found that BCL2-associated athanogene 6 (BAG6; also known as BAT3 or Scythe) is required for this process. Indeed, RNA interference-mediated depletion of endogenous BAG6 prevented Parkin-dependent relocalization of mitochondrial clusters to the perinuclear cytoplasmic region, whereas BAG6 knockdown did not affect the translocation of Parkin and p62/SQSTM1 to the depolarized mitochondria and subsequent aggregation. These results suggest that BAG6 is essential for cytoplasmic redistribution, but not for clustering, of damaged mitochondria.

Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy.

AIMS: To compare the occurrence of cerebral, cardiovascular, and renal events in patients with hyperuricaemia treated with febuxostat and those treated with conventional therapy with lifestyle modification. METHODS AND RESULTS: This multicentre, prospective, randomized open-label, blinded endpoint study was done in 141 hospitals in Japan. A total of 1070 patients were included in the intention-to-treat population. Elderly patients with hyperuricaemia (serum uric acid >7.0 to ≤9.0 mg/dL) at risk for cerebral, cardiovascular, or renal disease, defined by the presence of hypertension, Type 2 diabetes, renal disease, or history of cerebral or cardiovascular disease, were randomized to febuxostat and non-febuxostat groups and were observed for 36 months. Cerebral, cardiovascular, and renal events and all deaths were defined as the primary composite event. The serum uric acid level at endpoint (withdrawal or completion of the study) in the febuxostat (n = 537) and non-febuxostat groups (n = 533) was 4.50 ± 1.52 and 6.76 ± 1.45 mg/dL, respectively (P < 0.001). The primary composite event rate was significantly lower in the febuxostat group than in non-febuxostat treatment [hazard ratio (HR) 0.750, 95% confidence interval (CI) 0.592-0.950; P = 0.017] and the most frequent event was renal impairment (febuxostat group: 16.2%, non-febuxostat group: 20.5%; HR 0.745, 95% CI 0.562-0.987; P = 0.041). CONCLUSION: Febuxostat lowers uric acid and delays the progression of renal dysfunction. REGISTRATION: ClinicalTrials.gov (NCT01984749).

Risk Profile and 1-Year Outcome of Newly Diagnosed Atrial Fibrillation in Japan　- Insights From GARFIELD-AF.

BACKGROUND: Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective non-interventional study of stroke prevention in patients with newly diagnosed non-valvular AF (NAVF) that is being conducted in 35 countries. Methods and Results: A total of 52,081 patients with a new diagnosis of NVAF were enrolled prospectively in GARFIELD-AF. Of these, 4859 (9.3%) were recruited in Japan (2010-2016). In cohort 1 (2010-2011), few patients were on non-vitamin K antagonist oral anticoagulants (NOAC) globally. From cohort 2 onwards (2011-2016), however, there was a rapid increase in NOAC use around the globe, especially in Japan. By the last year of enrolment (2015-2016), 67.9% of patients in Japan and 43.1% of patients globally were on NOAC±antiplatelet therapy (AP). In Japan and globally, 17.0% and 12.2% of patients, respectively, did not receive stroke prevention treatment. Few patients in Japan (5.7%) received AP only. Compared with the other countries, the unadjusted rates of all-cause mortality and major bleeding were low, while rates of stroke/systemic embolism were similar after 1 year of follow-up. CONCLUSIONS: GARFIELD-AF continues to provide important information on the homogeneity and heterogeneity of baseline characteristics and treatment patterns in patients with newly diagnosed NVAF. This diversity reflects the differences in outcomes in Japan compared with the rest of the world.

Novel phosphorelay-dependent control of ZFP36L1 protein during the cell cycle.

The ZFP36 family is a prototypical member of a highly conserved group of proteins with CCCH-type RNA-binding domains, whose functional role and regulatory mechanism in mitotic cells remain obscure. In this study, we provide the first evidence that ZFP36L1 phosphorylation is modulated in a cell cycle-dependent manner. The C-terminal region of ZFP36L1 is critical for its cell cycle-dependent phosphorylation of this protein. We also suggest that the phosphorelay-dependent regulation of ZFP36L1 influences mitotic spindle organization. Thus, our data demonstrate a new class of regulatory mechanism for CCCH-type zinc-finger proteins in cell cycle control.

ZFP36L2 is a cell cycle-regulated CCCH protein necessary for DNA lesion-induced S-phase arrest.

ZFP36L2 promotes the destruction of AU-rich element-containing transcripts, while its regulation and functional significance in cell cycle control are scarcely identified. We show that ZFP36L2 is a cell cycle-regulated CCCH protein, the abundance of which is regulated post-translationally at the respective stages of the cell cycle. Indeed, ZFP36L2 protein was eliminated after release from M phase, and ZYG11B-based E3 ligase plays a role in its polyubiquitination in interphase. Although ZFP36L2 is dispensable for normal cell cycle progression, we found that endogenous ZFP36L2 played a key role in cisplatin-induced S-phase arrest, a process in which the suppression of G1/S cyclins is necessary. The accumulation of ZFP36L2 was stimulated under DNA replication stresses and altered interactions with a subset of RNA-binding proteins. Notably, silencing endogenous ZFP36L2 led to impaired cell viability in the presence of cisplatin-induced DNA lesions. Thus, we propose that ZFP36L2 is a key protein that controls S-phase progression in the case of genome instability.

Rationale, design, and baseline characteristics of a study to evaluate the effect of febuxostat in preventing cerebral, cardiovascular, and renal events in patients with hyperuricemia.

BACKGROUND: Since uric acid is associated with cardiovascular and renal disease, a treatment to maintain blood uric acid level may be required in patients with hyperuricemia. This study aims to evaluate preventive effects of febuxostat, a selective xanthine oxidase inhibitor, on cerebral, cardiovascular, and renal events in patients with hyperuricemia compared to conventional treatment. METHODS AND RESULTS: This study is a prospective randomized open-label blinded endpoint study. Patient enrolment was started in November 2013 and was completed in October 2014. The patients will be followed for at least 3 years. The primary endpoint is a composite of cerebral, cardiovascular, and renal events, and all deaths including death due to cerebral, cardiovascular, and renal disease, new or recurring cerebrovascular disease, new or recurring non-fatal coronary artery disease, cardiac failure requiring hospitalization, arteriosclerotic disease requiring treatment, renal impairment, new atrial fibrillation, and all deaths other than cerebral or cardiovascular or renal disease. These events will be independently evaluated by the Event Assessment Committee under blinded information regarding the treatment group. The study was registered at ClinicalTrials.gov with the identifier NCT01984749.

A conserved island of BAG6/Scythe is related to ubiquitin domains and participates in short hydrophobicity recognition.

BAG6 (also called Scythe) interacts with the exposed hydrophobic regions of newly synthesized proteins and escorts them to the degradation machinery through mechanisms that remain to be elucidated. In this study, we provide evidence that BAG6 physically interacts with the model defective protein substrate CL1 in a manner that depends directly on its short hydrophobicity. We found that the N terminus of BAG6 contains an evolutionarily conserved island tentatively designated the BAG6 ubiquitin-linked domain. Partial deletion of this domain in the BAG6 N-terminal fragment abolished in cell recognition of polyubiquitinated polypeptides as well as the hydrophobicity-mediated recognition of the CL1 degron in cell and in vitro. These observations suggest a mechanism whereby the BAG6 ubiquitin-linked domain provides a platform for discriminating substrates with shorter hydrophobicity stretches as a signal for defective proteins.

Differences in 24-h blood pressure profile of Japanese hypertensive patients under ARB treatment.

Blood pressure (BP) control throughout the entire day is recommended for cardiovascular protection. Angiotensin-II receptor blockers (ARBs) are widely used in hypertensive patients because of beneficial class effects. It is uncertain, however, whether are there any differences in 24-h BP profiles among ARBs. We examined ambulatory blood pressure monitoring (ABPM) among 211 Japanese hypertensive patients (age, 69.4 ± 9.6 years; female, 59.2%) under treatment with five different ARBs. Patients were divided into five groups according to ARBs prescribed. Patient backgrounds were almost identical in all the groups and there were no differences in office, 24-h and daytime BP; however, nighttime BP with olmesartan was significantly lower than with other ARBs. Office BPs with candesartan and telmisartan, but not other ARBs, correlated well with 24-h BP (p < 0.01). Also, there were higher correlations between daytime and nighttime BP with candesartan and telmisartan. In all patients, pulse pressure with office BP was significantly correlated with ambulatory arterial stiffness index (p = 0.001) and fluctuation of systolic BP on ABPM (p = 0.002). In conclusion, different ARB treatments produced meaningful differences in 24-h profiles.

Structure of a BAG6 (Bcl-2-associated athanogene 6)-Ubl4a (ubiquitin-like protein 4a) complex reveals a novel binding interface that functions in tail-anchored protein biogenesis.

BAG6 is an essential protein that functions in two distinct biological pathways, ubiquitin-mediated protein degradation of defective polypeptides and tail-anchored (TA) transmembrane protein biogenesis in mammals, although its structural and functional properties remain unknown. We solved a crystal structure of the C-terminal heterodimerization domains of BAG6 and Ubl4a and characterized their interaction biochemically. Unexpectedly, the specificity and structure of the C terminus of BAG6, which was previously classified as a BAG domain, were completely distinct from those of the canonical BAG domain. Furthermore, the tight association of BAG6 and Ubl4a resulted in modulation of Ubl4a protein stability in cells. Therefore, we propose to designate the Ubl4a-binding region of BAG6 as the novel BAG-similar (BAGS) domain. The structure of Ubl4a, which interacts with BAG6, is similar to the yeast homologue Get5, which forms a homodimer. These observations indicate that the BAGS domain of BAG6 promotes the TA protein biogenesis pathway in mammals by the interaction with Ubl4a.