Association of remnant cholesterol with risk of cardiovascular disease events, stroke, and mortality: A systemic review and meta-analysis.

BACKGROUND AND AIMS: Lipid disorders are associated with the risk of cardiovascular diseases (CVDs). Remnant cholesterol (RC), a non-traditional previously neglected risk factor for CVD, has received much attention in recent years. The aim of this study is to evaluate the association of RC with the risks of CVD, stroke, and mortality. METHODS: MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov, and Cochrane Central Register for Controlled Trials were searched. We included randomized controlled trials (RCTs), non-RCTs, and observational cohort studies assessing the association of RC with the risks of cardiovascular (CV) events, coronary heart disease (CHD), stroke, and mortality. RESULTS: Overall, 31 studies were included in this meta-analysis. Compared with low RC, elevated RC was associated with an increased risk of CVD, CHD, stroke, CVD mortality, and all-cause mortality (RR = 1.53, 95% CI 1.41-1.66; RR = 1.41, 95% CI 1.19-1.67; RR = 1.43, 95% CI 1.24-1.66; RR = 1.83, 95% CI 1.53-2.19; and RR = 1.39, 95% CI 1.27-1.50; respectively). A subgroup analysis demonstrated that each 1.0 mmol/L increase in RC was associated with an increased risk of CVD events and CHD. The association of RC with an increased CVD risk was not dependent on the presence or absence of diabetes, a fasted or non-fasted state, total cholesterol, or triglyceride or ApoB stratification. CONCLUSIONS: Elevated RC is associated with an increased risk of CVD, stroke, and mortality. In addition to the traditional cardiovascular risk factors, such as total cholesterol and LDL-C, clinicians should also pay attention to RC in clinics.

Statin use and the risk of CVD events, stroke, and all-cause mortality in patients with diabetes: A systematic review and meta-analysis.

AIMS: Considering the lack of evidence on statin use and the risk of cardiovascular disease (CVD) in patients with diabetes in primary and secondary prevention, this study aimed to evaluate the effect of statin use in individuals with diabetes for primary and secondary prevention. DATA SYNTHESIS: The MEDLINE, Web of Science, Embase, ClinicalTrials.gov, and Cochrane Central Register for Controlled Trials databases were searched. We included studies that assessed the effect of statin use in individuals with diabetes for at least 1 year. The outcomes included CVD, all-cause mortality, and stroke. A total of 24 studies including 2,152,137 patients with diabetes were included in the meta-analysis. Compared with statin non-users, patients who received statins showed a lower risk of CVD events (primary prevention: risk ratio [RR] = 0.80, 95% confidence interval [CI] 0.69-0.94, P = 0.006; secondary prevention: RR = 0.75, 95% CI 0.65-0.87, P < 0.0001). No association was observed between statin and non-statin users and the risk of all-cause mortality. The pooled results also revealed that statin use reduced the risk of ischemic stroke in patients with diabetes (primary prevention: RR = 0.83, 95% CI 0.70-0.97, P = 0.020; secondary prevention: RR = 0.74, 95% CI 0.63-0.85, P < 0.0001). CONCLUSIONS: Statin use significantly reduced the risk of CVD events and stroke, but not all-cause mortality, in individuals with diabetes undergoing both primary and secondary prevention. More data are required to verify the effects of statins in patients with diabetes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021281132.

Association of the Coexistence of Somnipathy and Diabetes With the Risks of Cardiovascular Disease Events, Stroke, and All-Cause Mortality: A Systematic Review and Meta-analysis.

Background Somnipathy and diabetes are independently associated with an increased risk of cardiovascular disease (CVD). However, whether a combination of both conditions is associated with a higher risk of CVD events remains uncertain. Therefore, the aim of this meta-analysis was to clarify this association. Methods and Results We searched MEDLINE, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register for Controlled Trials. We included randomized controlled trials, nonrandomized trials, and prospective observational cohort studies that assessed the combined effect of diabetes and comorbid somnipathy on CVD risk and mortality for at least 1 year. Outcomes included CVD, coronary heart disease, stroke, and all-cause mortality. Twelve studies involving 582 267 participants were included in the meta-analysis. Patients with somnipathy and comorbid diabetes exhibited increased risks of CVD, coronary heart disease, stroke, and all-cause mortality (risk ratio [RR], 1.27 [95% CI, 1.12-1.45], P<0.0001; RR, 1.40 [95% CI, 1.21-1.62], P<0.0001; RR, 1.28 [95% CI, 1.08-1.52], P=0.004, and RR, 1.56 [95% CI, 1.26-1.94], P<0.0001, respectively). Conclusions The coexistence of somnipathy and diabetes is associated with higher risks of CVD, coronary heart disease, stroke, and mortality than somnipathy or diabetes alone. Resolving sleep problems in patients with diabetes may reduce the risks of CVD, stroke, and mortality. Registration Information https://www.crd.york.ac.uk/prospero/. Identifier: PROSPERO CRD42021274566.

Cholesterol Stimulates the Transient Receptor Potential Melastatin 4 Channel in mpkCCDc14 Cells.

We have shown that cholesterol regulates the activity of ion channels in mouse cortical collecting duct (CCD) mpkCCDc14 cells and that the transient receptor potential melastatin 4 (TRPM4) channel is expressed in these cells. However, whether TRPM4 channel is regulated by cholesterol remains unclear. Here, we performed inside-out patch-clamp experiments and found that inhibition of cholesterol biosynthesis by lovastatin significantly decreased, whereas enrichment of cholesterol with exogenous cholesterol significantly increased, TRPM4 channel open probability (Po) by regulating its sensitivity to Ca2+ in mpkCCDc14 cells. In addition, inside-out patch-clamp data show that acute depletion of cholesterol in the membrane inner leaflet by methyl-ß-cyclodextrin (MßCD) significantly reduced TRPM4 Po, which was reversed by exogenous cholesterol. Moreover, immunofluorescence microscopy, Western blot, cell-surface biotinylation, and patch clamp analysis show that neither inhibition of intracellular cholesterol biosynthesis with lovastatin nor application of exogenous cholesterol had effect on TRPM4 channel protein abundance in the plasma membrane of mpkCCDc14 cells. Sucrose density gradient centrifugation studies demonstrate that TRPM4 was mainly located in cholesterol-rich lipid rafts. Lipid-protein overlay experiments show that TRPM4 directly interacted with several anionic phospholipids, including PI(4,5)P2. Depletion of PI(4,5)P2 with either wortmannin or PGE2 abrogated the stimulatory effects of exogenous cholesterol on TRPM4 activity, whereas exogenous PI(4,5)P2 (diC8-PI(4,5)P2, a water-soluble analog) increased the effects. These results suggest that cholesterol stimulates TRPM4 via a PI(4,5)P2-dependent mechanism.

Identification of differentially expressed genes in diabetic kidney disease by RNA-Seq analysis of venous blood platelets.

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. However, because of shared complications between DKD and chronic kidney disease (CKD), the description and characterization of DKD remain ambiguous in the clinic, hindering the diagnosis and treatment of early-stage DKD patients. Although estimated glomerular filtration rate and albuminuria are well-established biomarkers of DKD, early-stage DKD is rarely accompanied by a high estimated glomerular filtration rate, and thus there is a need for new sensitive biomarkers. Transcriptome profiling of kidney tissue has been reported previously, although RNA sequencing (RNA-Seq) analysis of the venous blood platelets in DKD patients has not yet been described. In the present study, we performed RNA-Seq analysis of venous blood platelets from three patients with CKD, five patients with DKD and 10 healthy controls, and compared the results with a CKD-related microarray dataset. In total, 2097 genes with differential transcript levels were identified in platelets of DKD patients and healthy controls, and 462 genes with differential transcript levels were identified in platelets of DKD patients and CKD patients. Through Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, we selected 11 pathways, from which nine potential biomarkers (IL-1B, CD-38, CSF1R, PPARG, NR1H3, DDO, HDC, DPYS and CAD) were identified. Furthermore, by comparing the RNA-Seq results with the GSE30566 dataset, we found that the biomarker KCND3 was the only up-regulated gene in DKD patients. These biomarkers may have potential application for the therapy and diagnosis of DKD, as well aid in determining the mechanisms underlying DKD.

Febuxostat Use and Risks of Cardiovascular Disease Events, Cardiac Death, and All-cause Mortality: Metaanalysis of Randomized Controlled Trials.

OBJECTIVE: To assess whether febuxostat use increases the risk of developing cardiovascular (CV) events, cardiac death, and all-cause mortalities. METHODS: The relevant literature was searched in several databases including MEDLINE (PubMed, January 1, 1966-February 29, 2020), Web of Science, EMBASE (January 1, 1974-February 29, 2020), ClinicalTrials. gov, and Cochrane Central Register of Controlled Trials. Manual searches for references cited in the original studies and relevant review articles were also performed. All studies included in this metaanalysis were published in English. RESULTS: In the end, 20 studies that met our inclusion criteria were included in our metaanalysis. Use of febuxostat was found not to be associated with an increased risk of all-cause mortality (RR 0.87, 95% CI 0.57-1.32, P = 0.51). Also, there was no association between febuxostat use and mortalities arising from CV diseases (CVD; RR 0.84, 95% CI 0.49-1.45, P = 0.53). The RR also revealed that febuxostat use was not associated with CVD events (RR 0.98, 95% CI 0.83-1.16, P = 0.83). Further, the likelihood of occurrence of CVD events was found not to be dependent on febuxostat dose (RR 1.04, 95% CI 0.84-1.30, P = 0.72). CONCLUSION: Febuxostat use is not associated with increased risks of all-cause mortality, death from CVD, or CVD events. Accordingly, it is a safe drug for the treatment of gout.

Endothelial epithelial sodium channel involves in high-fat diet-induced atherosclerosis in low-density lipoprotein receptor-deficient mice.

We previously showed that increased epithelial sodium channel (ENaC) activity in endothelial cells induced by oxidized low-density lipoprotein (ox-LDL) contributes to vasculature dysfunction. Here, we investigated whether ENaC participates in the pathological process of atherosclerosis using LDL receptor-deficient (LDLr-/-) mice. Male C57BL/6 and LDLr-/- mice were fed a normal diet (ND) or high fat diet (HFD) for 10 weeks. Our data show that treatment of LDLr-/- mice with a specific ENaC blocker, benzamil, significantly decreased atherosclerotic lesion formation and expression of matrix metalloproteinase 2 (MMP2) and metalloproteinase 9 (MMP9) in aortic arteries. Furthermore, benzamil ameliorated HFD-induced impairment of aortic endothelium-dependent dilation by reducing expression of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6 and production of adhesion molecules including VCAM-1 and ICAM-1 in both C57BL/6 and LDLr-/- mice fed with HFD. In addition, HFD significantly increased ENaC activity and the levels of serum lipids, including ox-LDL. Our in vitro data further demonstrated that exogenous ox-LDL significantly increased the production of TNF-α, IL-1ß, IL-6, VCAM-1 and ICAM-1. This ox-LDL-induced increase in inflammatory cytokines and adhesion molecules was reversed by γ-ENaC silencing or by treatment with the cyclooxygenase-2 (COX-2) antagonist celecoxib. Benzamil inhibited HFD-induced increase in COX-2 expression in aortic tissue in both C57BL/6 and LDLr-/- mice, and γ-ENaC gene silencing attenuated ox-LDL-induced COX-2 expression in HUVECs. These data together suggest that HFD-induced activation of ENaC stimulates inflammatory signaling, thereby contributes to HFD-induced endothelial dysfunction and atherosclerotic lesion formation. Thus, targeting endothelial ENaC may be a promising strategy to halt atherogenesis.

The Epidemiological Characteristics of Late-Onset Hypogonadism in Chinese Middle-Aged and Elderly Men: Two Cross-Sectional Studies in the Same Community.

The purpose of this study was to investigate the prevalence and epidemiological characteristics of late-onset hypogonadism (LOH) in middle-aged and elderly Chinese men. Two cross-sectional studies were conducted at 5-year intervals in community-dwelling men living in the same area. A total of 1472 (Study 1, S1) and 944 (Study 2, S2) men aged 40-69 years old were recruited as subjects. Subjects were evaluated through combining serum reproductive hormone levels with the Androgen Deficiency in Aging Males (ADAM) questionnaire and the Aging Males' Symptoms (AMS) scale. A significant difference was found in mean testosterone deficiency (TD) prevalence between S1 and S2, using either serum total testosterone (TT; 14.02% vs. 6.36%) or serum calculated free testosterone (cFT; 43.69% vs. 16.53%) cutoff values. According to the S1 or S2 data, the mean prevalence of LOH was 37.85%/15.47% in the positive ADAM test and 15.42%/9.43% in the positive AMS test (p < .01). According to classifications of TD based on gonadal status, the prevalence of secondary TD (27.34%) was higher than the primary (16.36%) and compensated (15.42%) TD in S1 (p < .01). However, there were significant differences among the prevalence of primary (6.89%), secondary (9.64%), and compensated (27.65%) TD in S2 (p < .05). Different types of testosterone levels, TD cutoff values, and questionnaires influenced the prevalence of TD and LOH. The serum FT cutoff value was an optimal threshold for evaluating and diagnosing TD and LOH, whose prevalence increased gradually with male aging.

EGCG Attenuates Renal Damage via Reversing Klotho Hypermethylation in Diabetic db/db Mice and HK-2 Cells.

To explore whether epigallocatechin-3-gallate (EGCG) improves renal damage in diabetic db/db mice and high-glucose- (HG-) induced injury in HK-2 cells by regulating the level of Klotho gene promoter methylation. Western blotting was used to detect the protein expression levels of DNA methyltransferase 1 (DNMT1), DNMT3a, DNMT3b, transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin (α-SMA), and Klotho. The methylation level of the Klotho gene promoter was detected by pyrosequencing. Chromatin immunoprecipitation was used to detect the binding of the Klotho gene promoter to DNMT1 and DNMT3a. The expression of oxidative stress markers (reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), and 8-hydroxy-2'-deoxyguanosine (8-OHdG)) and inflammatory cytokines (interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α)) in kidney homogenates was also measured using ELISA. Klotho and DNMT3b protein expression was upregulated, while DNMT1, DNMT3a, TGF-ß1, and α-SMA protein expression was downregulated after EGCG treatment. EGCG treatment also reduced the methylation level of the Klotho gene promoter as well as the binding of DNMT3a to the Klotho gene promoter. In addition, EGCG treatment significantly decreased the levels of ROS, MDA, 8-OHdG, IL-1ß, IL-6, and TNF-α and increased the levels of CAT and SOD. Under HG conditions, EGCG regulated Klotho gene promoter methylation via DNMT3a and decreased the methylation level of the Klotho gene promoter, thereby upregulating the expression of the Klotho protein to exert its protective effect.

Age-related changes in serum reproductive hormone levels and prevalence of androgen deficiency in Chinese community-dwelling middle-aged and aging men: Two cross-sectional studies in the same population.

To investigate the age-related nomograms and change trends of reproductive hormones, and prevalence of androgen deficiency (AD) in middle-aged and aging men from 2 studies.Two cross-sectional studies were conducted at 5-year intervals in Chinese community-dwelling men living in the same area. A total of 434 (Study 1, S1) and 944 (Study 2, S2) men aged 40 to 69 years were recruited as subjects and 59 (S1) and 98 (S2) men aged 20 to 39 years as controls to measure serum reproductive hormone levels.Serum total testosterone (TT) levels did not change significantly in S1, whereas TT levels increased in S2 with aging. Serum calculated free testosterone (cFT) levels gradually decreased with aging; however, only men aged 40 to 69 years showed this trend in S2. Serum luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels gradually increased, and serum testosterone secretion index (TSI) and free testosterone index (FTI) levels gradually decreased with male aging. The mean annual decrease values of serum cFT were 2.705 pmol/l in S1 and 1.060 pmol/l in S2. The cut-off values for AD in S1 and S2 were 9.13 nmol/l and 9.35 nmol/l for TT, and 169.00 pmol/l and 213.90 pmol/l for cFT. Using TT or cFT cut-off values, mean AD prevalence was 14.52% or 44.70% in S1, and 6.36% or 16.53% in S2. Based on cFT cut-off values, prevalence of AD increased gradually with male aging in a range of 25.30% to 61.63% in S1 and 1.20% to 23.03% in S2.The change patterns of serum LH, SHBG, TSI and FTI levels in middle-aged and aging males were consistent; however, there were differences in serum TT and cFT change patterns in S1 and S2 with male aging. cFT cut-off values were the optimal metric to evaluate AD, which can be present a ladder-like change in prevalence of different age groups.

Lovastatin attenuates hypertension induced by renal tubule-specific knockout of ATP-binding cassette transporter A1, by inhibiting epithelial sodium channels.

BACKGROUND AND PURPOSE: We have shown that cholesterol is synthesized in the principal cells of renal cortical collecting ducts (CCD) and stimulates the epithelial sodium channels (ENaC). Here we have determined whether lovastatin, a cholesterol synthesis inhibitor, can antagonize the hypertension induced by activated ENaC, following deletion of the cholesterol transporter (ATP-binding cassette transporter A1; ABCA1). EXPERIMENTAL APPROACH: We selectively deleted ABCA1 in the principal cells of mouse CCD and used the cell-attached patch-clamp technique to record ENaC activity. Western blot and immunofluorescence staining were used to evaluate protein expression levels. Systolic BP was measured with the tail-cuff method. KEY RESULTS: Specific deletion of ABCA1 elevated BP and ENaC single-channel activity in the principal cells of CCD in mice. These effects were antagonized by lovastatin. ABCA1 deletion elevated intracellular cholesterol levels, which was accompanied by elevated ROS, increased expression of serum/glucocorticoid regulated kinase 1 (Sgk1), phosphorylated neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2) and furin, along with shorten the primary cilium, and reduced ATP levels in urine. CONCLUSIONS AND IMPLICATIONS: These data suggest that specific deletion of ABCA1 in principal cells increases BP by stimulating ENaC channels via a cholesterol-dependent pathway which induces several secondary responses associated with oxidative stress, activated Sgk1/Nedd4-2, increased furin expression, and reduced cilium-mediated release of ATP. As ABCA1 can be blocked by cyclosporine A, these results suggest further investigation of the possible use of statins to treat CsA-induced hypertension.

Association of sleep disorders, chronic pain, and fatigue with survival in patients with chronic kidney disease: a meta-analysis of clinical trials.

OBJECTIVE: Sleep disorders, chronic pain, and fatigue have been long-standing torments in most patients with chronic kidney disease (CKD). In this review, we attempted to explore whether these nontraditional cardiovascular risk factors are associated with increased mortality in patients with CKD. METHOD: Electronic searches were performed in MEDLINE (PubMed, 1966-2018), EMBASE (1974-2018), ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials databases. All prospective or retrospective studies were considered eligible if they were cohort or observational studies and the final outcome was all-cause death or mortality. RESULTS: We ultimately included 18 studies (12 studies on sleep disorders, three studies on chronic pain, and three studies on fatigue) in our review. Pooled analysis of all studies indicated that patients with sleep disorders, chronic pain, and fatigue had increased risks of all-cause mortality (risk ratio [RR] = 1.47, 95% confidence interval [CI] = 1.30-1.66, p < 0.0001; RR = 1.29, 95% CI = 1.27-1.31, p < 0.0001; RR = 1.45, 95% CI = 1.23-1.70, p < 0.0001, respectively). Pooled results from four studies indicated that dialysis patients with sleep-disordered breathing had increased cardiovascular disease outcomes (RR = 2.45, 95% CI = 1.74-3.44, p < 0.0001). CONCLUSION: Sleep disorders, chronic pain, and fatigue are remarkably associated with increased all-cause mortality in patients with CKD. Large clinical randomized controlled trials are required to further confirm the results of our meta-analysis.

TRUSS Exacerbates NAFLD Development by Promoting IκBα Degradation in Mice.

There is no effective treatment method for nonalcoholic fatty liver disease (NAFLD), the most common liver disease. The exact mechanism underlying the pathogenesis of NAFLD remains to be elucidated. Here, we report that tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein (TRUSS) acts as a positive regulator of NAFLD and in a variety of metabolic disorders. TRUSS expression was increased in the human liver specimens with NAFLD or nonalcoholic steatohepatitis, and in the livers of high-fat diet (HFD)-induced and genetically obese mice. Conditional knockout of TRUSS in hepatocytes significantly ameliorated hepatic steatosis, insulin resistance, glucose intolerance, and inflammatory responses in mice after HFD challenge or in spontaneous obese mice with normal chow feeding. All of these HFD-induced pathological phenotypes were exacerbated in mice overexpressing TRUSS in hepatocytes. We show that TRUSS physically interacts with the inhibitor of nuclear factor κB α (IκBα) and promotes the ubiquitination and degradation of IκBα, which leads to aberrant activation of nuclear factor κB (NF-κB). Overexpressing IκBαS32A/S36A , a phosphorylation-resistant mutant of IκBα, in the hepatocyte-specific TRUSS overexpressing mice almost abolished HFD-induced NAFLD and metabolic disorders. Conclusion: Hepatocyte TRUSS promotes pathological stimuli-induced NAFLD and metabolic disorders, through activation of NF-κB by promoting ubiquitination and degradation of IκBα. Our findings may provide a strategy for the prevention and treatment of NAFLD by targeting TRUSS.

Highly efficient generation of 0.2 mJ terahertz pulses in lithium niobate at room temperature with sub-50 fs chirped Ti:sapphire laser pulses.

We demonstrate generation of 0.2 mJ terahertz (THz) pulses in lithium niobate driven by Ti:sapphire laser pulses at room temperature. Employing tilted pulse front technique, the 800 nm-to-THz energy conversion efficiency has been optimized to 0.3% through chirping the sub-50 fs pump laser pulses to overcome multi-photon absorption and to extend effective interaction length for phase matching. Our approach paves the way for mJ-level THz generation via optical rectification using existing Ti:sapphire laser systems which can deliver Joule-level pulse energy with sub-50 fs pulse duration.

An aorto-oesophageal fistula caused by a fish bone resulting in an accidental discovery of an invasive adenocarcinoma in the lung.

An aorto-oesophageal fistula is a rare, life-threatening complication caused by sharp foreign bodies in the oesophagus. We report an aorto-oesophageal fistula in the inferior segment of thoracic oesophagus caused by a fish bone. Multiplanar reconstruction of computed tomography and computed tomography angiography demonstrated that a foreign body had pierced from the left posterior wall of the oesophagus into the descending aortic wall. These computed tomography images can help radiologists make the correct diagnosis and provide precise evidence for clinicians to perform a timely surgical intervention. In addition, a nodule in the upper lobe of the left lung was found by accident. The pathological finding after surgery revealed an invasive adenocarcinoma.

Oxidized low-density lipoprotein stimulates epithelial sodium channels in endothelial cells of mouse thoracic aorta.

BACKGROUND AND PURPOSE: The epithelial sodium channel (ENaC) is expressed in endothelial cells and acts as a negative modulator of vasodilatation. Oxidized LDL (ox-LDL) is a key pathological factor in endothelial dysfunction. In the present study we examined the role of ENaC in ox-LDL-induced endothelial dysfunction and its associated signal transduction pathway. EXPERIMENTAL APPROACH: Patch clamp techniques combined with pharmacological approaches were used to examine ENaC activity in the endothelial cells of a split-open mouse thoracic aorta. Western blot analysis was used to determine ENaC expression in the aorta. The aorta relaxation was measured using a wire myograph assay. KEY RESULTS: Ox-LDL, but not LDL, significantly increased ENaC activity in the endothelial cells attached to split-open thoracic aortas, and the increase was inhibited by a lectin-like ox-LDL receptor-1 (LOX-1) antagonist (κ-carrageenan), an NADPH oxidase inhibitor (apocynin), and a scavenger of ROS (TEMPOL). Sodium nitroprusside, an NO donor, diminished the ox-LDL-mediated activation of ENaC, and this effect was abolished by inhibiting soluble guanylate cyclase (sGC) and PKG. Ox-LDL reduced the endothelium-dependent vasodilatation of the aorta pectoralis induced by ACh, and this reduction was partially restored by blocking ENaC. CONCLUSION AND IMPLICATIONS: Ox-LDL stimulates ENaC in endothelial cells through LOX-1 receptor-mediated activation of NADPH oxidase and accumulation of intracellular ROS. Since the stimulation of ENaC can be reversed by elevating NO, we suggest that both inhibition of ENaC and an elevation of NO may protect the endothelium from ox-LDL-induced dysfunction. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

ZNF307 (Zinc Finger Protein 307) Acts as a Negative Regulator of Pressure Overload-Induced Cardiac Hypertrophy.

Pathological cardiac hypertrophy is a key risk factor for heart failure. We found that the protein expression levels of the ZNF307 (zinc finger protein 307) were significantly increased in heart samples from both human patients with dilated cardiomyopathy and mice subjected to aortic banding. Therefore, we aimed to elucidate the role of ZNF307 in the development of cardiac hypertrophy and to explore the signal transduction events that mediate the effect of ZNF307 on cardiac hypertrophy, using cardiac-specific ZNF307 transgenic (ZNF307-TG) mice and ZNF307 global knockout (ZNF307-KO) mice. The results showed that the deletion of ZNF307 potentiated aortic banding-induced pathological cardiac hypertrophy, fibrosis, and cardiac dysfunction; however, the aortic banding-induced cardiac hypertrophic phenotype was dramatically diminished by ZNF307 overexpression in mouse heart. Mechanistically, the antihypertrophic effects mediated by ZNF307 in response to pathological stimuli were associated with the direct inactivation of NF-κB (nuclear factor-κB) signaling and blockade of the nuclear translocation of NF-κB subunit p65. Furthermore, the overexpression of a degradation-resistant mutant of IκBα (IκBαS32A/S36A) reversed the exacerbation of cardiac hypertrophy, fibrosis, and dysfunction shown in aortic banding-treated ZNF307-KO mice. In conclusion, our findings demonstrate that ZNF307 ameliorates pressure overload-induced cardiac hypertrophy by inhibiting the activity of NF-κB-signaling pathway.

AP2/ERF Transcription Factors Involved in Response to Tomato Yellow Leaf Curly Virus in Tomato.

Tomato yellow leaf curly virus (TYLCV), transmitted by the whitefly (), causes leaf curling and yellowing, plant dwarfism, and growth inhibition in tomato ( L.). The APETALA2 (AP2) and ethylene response factor (ERF) transcription factor (TF) family, the largest plant-specific TF family, was identified to function in plant development and pathogen defense. Our study aimed to analyze the mechanism underlying the function of ERF (SlERF) TFs in response to TYLCV infection and improve useful information to increase the resistance to TYLCV in tomato. A total of 22 tomato AP2/ERF TFs in response to TYLCV were identified according to transcriptome database. Five ERF-B3 TFs were identified in cultivars Hongbeibei (highly resistant), Zheza-301, Zhefen-702 (both resistant), Jinpeng-1, and Xianke-6 (both susceptible). Interaction network indicated that SlERF TFs could interact with mitogen-activated protein kinase (MAPK). Expression profiles of five ERF-B3 genes (, , , , and ) were detected by quantitative real-time-polymerase chain reaction (qRT-PCR) after TYLCV infection in five tomato cultivars. expression was upregulated in five tomato cultivars. The expressions of three genes (, , and ) were upregulated in Zheza-301 and Zhefen-702. and expressions were downregulated in Hongbeibei and Xianke-6, respectively. Yeast one-hybrid showed that the GCC-box binding ability of ERF-B3 TFs differed in resistant and susceptible tomato cultivars. Expression profiles were related to the GCC-box binding ability of SlERF TFs in resistant and susceptible tomato cultivars. The defense mechanism underlying the tomato's response to TYLCV involved a complicated network, which provided important information for us in breeding and genetic analysis.

Epigallocatechin-3-gallate Attenuates Renal Damage by Suppressing Oxidative Stress in Diabetic db/db Mice.

Epigallocatechin-3-gallate (EGCG), extracted from green tea, has been shown to have antioxidative activity. In the present study, we evaluated the effect of EGCG on the kidney function in db/db mice and also tried to investigate the underlying mechanism of the renoprotective effects of EGCG in both animals and cells. EGCG treatment could decrease the level of urinary protein, 8-iso-PGF2a, and Ang II. Moreover, EGCG could also change the level of several parameters associated with oxidative stress. In addition, the protein expression levels of AT-1R, p22-phox, p47-phox, p-ERK1/2, p-p38 MAPK, TGF-ß1, and α-SMA in diabetic db/db mice were upregulated, and all of these symptoms were downregulated with the treatment of EGCG at 50 and 100 mg/kg/d. Furthermore, the pathological changes were ameliorated in db/db mice after EGCG treatment. HK-2 cell-based experiments indicated that EGCG could inhibit the expression of MAPK pathways, which is the downstream effector of Ang II mediated oxidative stress. All these results indicated that EGCG treatment could ameliorate changes of renal pathology and delay the progression of DKD by suppressing hyperglycemia-induced oxidative stress in diabetic db/db mice.