ATP-binding cassette transporter G1 (ABCG1) is a cellular transmembrane protein that transports oxysterol efflux from cells to high-density lipoprotein (HDL) particles in the plasma. Previous studies have demonstrated that an ABCG1 deficiency exerts an antiatherosclerotic function through the effects of oxysterol accumulation in cells to enhance apoptosis and regulate inflammatory processes. However, whether the deficiency of ABCG1 and the corresponding changes in the efflux of oxysterols could take a series of impacts on the proteomic composition of HDL remains unclear. Here, plasma HDL of ABCG1(-/-) mice and their wild-type controls on a normal chow diet (NCD) or a high-fat diet (HFD) were isolated by ultracentrifugation. The proportion of 7-ketocholesterol and the proteomic composition of samples were comparatively analyzed by LC-MS/MS. In NCD-fed mice, lipid metabolism-related protein (arachidonate 12-lipoxygenase) and antioxidative protein (pantetheinase) exhibited increased accumulation, and inflammatory response protein (alpha-1-antitrypsin) was decreased in accumulation in ABCG1(-/-) mice HDL. In HFD-fed mice, fewer proteins were detected than that of NCD-fed mice. The ABCG1(-/-) mice HDL exhibited increased accumulation of lipid metabolism-related proteins (e.g., carboxylesterase 1C, apolipoprotein (apo)C-4) and decreased accumulation of alpha-1-antitrypsin, as well as significantly reduced proportion of 7-ketocholesterol. Additionally, positive correlations were found between 7-ketocholesterol and some essential proteins on HDL, such as alpha-1-antitrypsin, apoA-4, apoB-100, and serum amyloid A (SAA). These results suggest a detrimental impact of oxysterols on HDL composition, which might affect the antiatherosclerotic properties of HDL.

Salt-sensitive hypertension is closely related to inflammation, but the mechanism is barely known. Transmembrane member 16A (TMEM16A) is the Ca2+-activated chloride channel in epithelial cells, smooth muscle cells, and sensory neurons. It can promote inflammatory responses by increasing proinflammatory cytokine release. Here, we identified a positive role of TMEM16A in vascular inflammation. The expression of TMEM16A was increased in high-salt-stimulated vascular smooth muscle cells (VSMCs), whereas inhibiting TMEM16A or silencing TMEM16A with small interfering RNA (siRNA) can abolish this effect in vitro or in vivo. Transcriptome analysis of VSMCs revealed some differential downstream genes of TMEM16A related to inflammation, such as endothelial cell-specific molecule 1 (ESM1) and CXC chemokine ligand 16 (CXCL16). Overexpression of TMEM16A in VSMCs was accompanied by high levels of ESM1, CXCL16, intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1). We treated VSMCs cultured with high salt and arctigenin (ARC), T16Ainh-A01 (T16), and TMEM16A siRNA (siTMEM16A), leading to greatly decreased ESM1, CXCL16, VCAM-1, and ICAM-1. Beyond that, silencing ESM1, the expression of VCAM-1 and ICAM-1, and CXCL16 was attenuated. In conclusion, our results outlined a signaling scheme that increased TMEM16 protein upregulated ESM1, which possibly activated the CXCL16 pathway and increased VCAM-1 and ICAM-1 expression, which drives VSMC inflammation. Beyond that, arctigenin, as a natural inhibitor of TMEM16A, can reduce the systolic blood pressure (SBP) of salt-sensitive hypertension mice and alleviate vascular inflammation.

Abstract Vascular remodeling is a pathological basis of various disorders. Therefore, it is necessary to understand the occurrence, prevention, and treatment of vascular remodeling. Krüppel-like factor 5 (KLF5) has been identified as a significant factor in cardiovascular diseases during the last two decades. This review provides a mechanism network of function and regulation of KLF5 in vascular remodeling based on newly published data and gives a summary of its potential therapeutic applications. KLF5 modulates numerous biological processes, which play essential parts in the development of vascular remodeling, such as cell proliferation, phenotype switch, extracellular matrix deposition, inflammation, and angiogenesis by altering downstream genes and signaling pathways. Considering its essential functions, KLF5 could be developed as a potent therapeutic target in vascular disorders.

目的 测定巨噬细胞ABCG1介导的氧化固醇外流情况.方法 利用ABCG1基因小干扰RNA慢病毒表达载体感染THP-1细胞,经有限稀释法筛选出敲低单克隆稳转株;用PMA诱导THP-1为巨噬细胞,ox-LDL(50μg/ml)刺激24 h后,通过液相色谱串联质谱测定细胞氧化固醇7β-羟基胆固醇(7β-OHC)和7-酮基胆固醇(7-KC)外流情况.结果 对待测样品进行了氧化固醇定性与定量分析,发现与无外流接受体的空白对照组相比,诱导氧化型胆固醇外流率增加(7-KC:28.6％±2.3％比4.1％±0.7％,P<0.001;7β-OHC:35.5％±5.7％比3.7％±1.1％,P<0.001).与阴性对照组相比,ABCG1敲低组氧化型胆固醇的外流率降低(7-KC:16.1％±3.1％比24.7％±2.3％,P<0.05;7β-OHC:15.7％±0.7％比33.1％±3.7％,P<0.001).胞内氧化固醇沉积量通过细胞总蛋白进行校正,结果显示,与对照组比较,ABCG1低表达巨噬细胞胞内氧化固醇沉积增加[7-KC:(6.61±1.28)μg/mg比(2.13±0.08)μg/mg,P<0.05;7β-OHC:(1.61±0.51)μg/mg比(0.65±0.20)μg/mg,P<0.05].结论 巨噬细胞ABCG1低表达可抑制氧化固醇7β-OHC及7-KC外流,增加胞内氧化固醇沉积.

Vascular remodeling is a pathological basis of various disorders.Therefore,it is necessary to understand the occurrence,prevention,and treatment of vascular remodeling.Krüppel-like factor 5 (KLF5) has been identified as a significant factor in cardio-vascular diseases during the last two decades.This review provides a mechanism network of function and regulation of KLF5 in vascular remodeling based on newly published data and gives a summary of its potential therapeutic applications.KLF5 modulates numerous biological processes,which play essential parts in the development of vascular remodeling,such as cell proliferation,phenotype switch,extracellular matrix deposition,inflammation,and angiogenesis by altering downstream genes and signaling pathways.Considering its essential functions,KLF5 could be developed as a potent therapeutic target in vascular disorders.

Vascular remodeling is a pathological basis of various disorders. Therefore, it is necessary to understand the occurrence, prevention, and treatment of vascular remodeling. Kruppel-like factor 5 (KLF5) has been identified as a significant factor in cardiovascular diseases during the last two decades. This review provides a mechanism network of function and regulation of KLF5 in vascular remodeling based on newly published data and gives a summary of its potential therapeutic applications. KLF5 modulates numerous biological processes, which play essential parts in the development of vascular remodeling, such as cell proliferation, phenotype switch, extracellular matrix deposition, inflammation, and angiogenesis by altering downstream genes and signaling pathways. Considering its essential functions, KLF5 could be developed as a potent therapeutic target in vascular disorders.

目的探讨盐摄入量与老年难治性高血压（RH）患者诊室血压及家庭自测血压（HBPM）达标的相关性及可能的机制。方法横断面研究我院老年RH患者100例,观察患者使用降压药物数量,测量诊室血压及HBPM,检查24h尿钠水平。将Dahl盐敏感大鼠20只随机分别予正常盐组及高盐组饲料喂养,每组10只。饮食干预12周后,使用微血管张力测定仪检测肠系膜阻力动脉（MRA）对去甲肾上腺素（NE）及血管紧张素Ⅱ（AngⅡ）的反应性,包括血管收缩能力及收缩维持能力。结果 100例RH患者24h尿钠平均水平为（175.24±79.76）mmol。低、低-中、中-高及高尿钠患者（各为25例）使用降压药物种类呈显著增多趋势[（3.52±0.65）种vs （3.68±0.75）种vs（3.80±0.76）种vs （3.96±0.78）种,P=0.031]。多因素logistic回归分析显示,诊室血压与24h尿钠水平和≥4种药物独立相关（P＜0.05）,清晨及上午HBPM与24h尿钠水平独立相关（P＜0.05）。高盐饮食12周后,与正常盐组比较,高盐组收缩压及舒张压明显升高（P＜0.01）。2组大鼠MRA对NE和AngⅡ的基本张力比较,无统计学差异（P＞0.05）。与正常盐组比较,高盐组大鼠MRA对NE的收缩绝对值、最大收缩斜率明显增加,达峰时间明显缩短,5min内松弛绝对值及松弛相对程度明显降低（P＜0.05,P＜0.01）,对AngⅡ的收缩绝对值明显增加（P＜0.05）。而2组大鼠MRA对AngⅡ的达峰时间、最大收缩斜率、5min内松弛绝对值及松弛相对程度无统计学差异（P＞0.05）。结论高盐饮食是影响老年RH患者应激状态下血压达标的独立因素,而MRA对升压物质的反应性增加可能是其作用机制。

目的 分析24 h尿钠排泄与难治性高血压(resistant hypertension,RH)患者诊室血压及家庭自测血压(home blood pressure monitoring,HBPM)达标状态的关系.方法 通过北京协和医院心内科门诊RH数据库,收集2017年10月至2018年3月间在北京协和医院心内科门诊就诊的RH患者临床资料,进行横断面调查.检测患者24 h尿钠,记录患者同期诊室血压、HBPM水平及临床用药情况,以所有患者24 h尿钠水平四分位数为分界点,将研究对象分为低尿钠、 低-中尿钠、 中-高尿钠及高尿钠4组.采用多因素Logistic回归,分析影响RH血压达标状态的危险因素.结果 共202例RH患者入选本研究,男性107例,女性95例,平均年龄(59.87±16.30)岁.24 h尿钠平均水平为(198.92±96.59)mmol,年轻患者及体质量指数高者尿钠水平更高(P均<0.001).随尿钠升高,降压药物的服用种类显著增多(P=0.001),早晨及上午的HBPM达标率低(P=0.040,0.032).多因素Logistic回归分析显示,24 h尿钠水平与诊室血压(OR=2.356,95％CI:1.004～5.533,P=0.049),HBPM早晨血压(OR=2.408,95％CI:1.026～5.650,P=0.030)及HBPM上午血压(OR=2.299,95％CI:1.031～5.129,P=0.033)达标状态独立相关,而与下午及夜间HBPM血压达标状态无显著相关(P均>0.05).结论 24 h尿钠是RH患者诊室血压及HBPM早晨及上午血压达标的独立相关因素,限制钠盐摄入对减少RH患者血压波动、 促进血压达标有重要作用.

The effects of high sodium intake on the functionality of resistance arteries have been repeatedly studied in vitro, but no study has focused on salt-sensitive hypertension in vivo. We studied the in vivo reactivity of mesenteric small arteries (MSAs) to vasoactive agents in Dahl salt-sensitive (DS) rats with various sodium diets. Twenty-four male DS rats were randomized into 3 groups: LS (0.3% NaCl diet), NS (0.6% NaCl diet), and HS (8% NaCl diet). After a 12-week intervention, the diameter changes of the MSAs after noradrenaline (NA) and acetylcholine (ACh) exposure were detected by a microscope, and changes in blood perfusion through the MSAs were measured by full-field laser perfusion imaging. HS enhanced the constrictive response of the MSAs to NA and attenuated the relaxing response to ACh. Low sodium intake reduced the response of the MSAs to NA and promoted ACh-induced vasodilatation. HS also aggravated NA-induced blood perfusion reduction and impaired ACh-induced hyperperfusion of the MSAs. Pathologically, HS was associated with arteriolar structural damage and fibrosis of the MSAs. We conclude that sodium intake affects the responsiveness of the MSAs to vasoactive agents in DS rats and might play important roles in modulating blood pressure in hypertensive individuals.

Objectives: To investigate the effect of sodium intake on the vasoconstrictive function of mesenteric small artery (MSA) in Dahl salt-sensitive (DS) rats. Methods: 24 8-week male DS rats were randomized into 4 groups and administrated with normal sodium (0.6% NaCl, NS group), lower sodium (0.3% NaCl, LS group), high sodium (8% NaCl, HS group) diet, and high sodium plus benazepril (10 mg/kg/d, HB group) treatment, respectively. Full-field laser perfusion imaging (LPI) and moorFLPI software were used to record blood flow and noradrenaline (NA, 10 μg/kg)-induced vasoconstriction in MSA. The diameter of MSA was recorded in situ and in vivo before and after NA injection by a high-speed camera with a microscope. Results: After a 6-week dietary intervention, compared with that in NS group, NA-induced MSA vasoconstriction in HS group was significantly enhanced (34.90 ± 15.46% vs. 18.61 ± 5.41%, P = 0.0495), while there was no difference between NS and HB group (P = 0.1396). Compared with that in NS group, NA-induced MSA blood perfusion in HS group significantly attenuated (33.28 ± 5.59% vs. 21.83 ± 7.22%, P = 0.0036), and there was no difference between HB and NS group (24.78 ± 11.29% vs. 21.83 ± 7.22%). NA-induced maximum decline of MSA blood perfusion was no difference among NS, LS and HB group (P > 0.05), while greater in HS than that in LS group (45.74 ± 10.17% vs. 26.89 ± 9.54%, P = 0.0367). Conclusion: High sodium intake enhanced the vasoconstrictive function of MSA in vivo, which could not be significantly ameliorated by benazepril. The results addressed the important role of high sodium intake in the hyperresponsiveness of small artery to catecholamine in hypertension.

Objectives: To study the effect of low sodium diet on the functional vasoconstriction of the mesenteric small artery (MSA) in Dahl salt-sensitive (DS) rats. Methods: 24 8-week male DS rats were randomized into four groups: normal sodium (NS), low sodium (LS), high sodium (HS), and high sodium followed by low sodium (HL) group. The first three groups were given 12-week diet with 0.6%, 0.3% and 8% of NaCl respectively, while the HL group was given 6-week high sodium diet followed by 6-week low sodium diet. After 12-week diet intervention, the diameter of MSA was recorded in situ and in vivo before and after NA injection (10 &mgr;g/kg) by a high-speed camera (GigaView camera, USA) with a microscope (BX51W1, OLYMPUS, Japan). Vasoconstriction was presented as the reduction of MSA diameter after NA injection divided by the diameter at baseline. Results: After 12-week diet intervention, compared with that in NS group, NA-induced vasoconstriction of MSA significantly enhanced in HS (50.48 ± 11.34% vs. 22.92 ± 2.43%, P = 0.0005) and HL group (34.13 ± 10.27% vs. 22.92 ± 2.43%, P = 0.0423). The percentage ratio was significantly lower in HL than that in HS group (34.13 ± 10.27% vs. 50.48 ± 11.34%, P = 0.0251). The duration of vasoconstriction was significantly longer in HS than that in NS (51.6 ± 17.5 s vs. 24.7 ± 3.7 s, P = 0.0086) and HL group (26.0 ± 5.5 s vs. 24.7 ± 3.7 s, P = 0.0086), while in LS, was shorter than that in NS group (16.2 ± 3.2 s vs. 24.7 ± 3.7 s, P = 0.0016). Conclusion: Change from high to low sodium diet improved the vasoconstrictive function of MSA in DS rats. Our results emphasized the significant role of sodium restriction in overcoming the hyperresponsiveness of small artery to catecholamine in hypertension.

Objectives: To study the effect of low sodium diet on the functional vasodilatation of mesenteric small artery (MSA) in Dahl salt-sensitive (DS) rats. Methods: 24 8-week male DS rats were randomized into 4 groups: normal sodium (NS), low sodium (LS), high sodium (HS), and high sodium followed by low sodium (HL) group. The first three groups were given 12-week diet with 0.6%, 0.3% and 8% of NaCl respectively, while the HL group was given 6-week HS diet followed by 6-week LS diet. MSA inner diameter recorded by GigaView high-speed camera was used to evaluate the acetylcholine (10ug/kg, Ach)-induced vasodilatation in situ and in vivo. Results: Our previous work showed that 6-week high sodium diet significantly impaired Ach-induced MSA vasodilatation compared with normal diet in DS rats (P < 0.05). In present study, after 12-week dietary intervention, compared to that in NS group, Ach-induced MSA vasodilatation in LS and HL group significantly enhanced (100.34 ± 26.17% and 60.43 ± 13.86% vs. 44.27 ± 4.67%, P < 0.01, P < 0.05 respectively), while in HS group significantly attenuated (17.27 ± 5.41% vs. 44.27 ± 4.67%, P < 0.001) (Fig. 1A). After first 6-week high sodium diet, 6-week sodium restriction in HL group dramatically improved the vasodilatation in comparison to HS group (P < 0.001). The duration of Ach-induced vasodilatation also shortened in HS when compared with that in NS group (21.23 ± 8.18 s vs. 36.83 ± 5.83 s, P < 0.05), however, it was significantly longer in HL than that in HS group (37.05 ± 11.26 s vs. 21.23 ± 8.18 s, P = 0.018) (Fig. 1B). Conclusion: High sodium intake severely impaired small artery vasodilatation in DS rats, which could be abolished by sodium restriction. Our findings highlighted the importance of sodium restriction on arterial function and hypertension treatment.

Objectives: This study aimed to examine the association between daily sodium intake and the blood pressure (BP) control in resistant hypertension (RH). Methods: We consecutively recruited 147 RH patients (47.6% male, age 54.14 ± 16.15 years) who received at least three antihypertensive drugs (Anti-HD) including diuretics. 24-hour urinary sodium excretion (24h-UNa) was tested to estimate the daily sodium intake. Home BP monitoring (HBPM) consisted of 4 measurements daily (before medicine in the morning, 10 a.m., 4 p.m., before sleeping at night). Office BP was recorded between 8 to 10 a.m. before taking medicine. Ambulatory BP monitoring (ABPM) was obtained for each patient. Multiple logistic regression analysis was performed, the variables including age > 65 years, sex, education, BMI≥28 kg/m2, waist circumstance, alcohol consumption, current smoking, eGFR, 24h-UNa, use of spironolactone and quantity of Anti-HD. The high, medium, and low 24h-UNa were defined as > 200mmol/24 h, 100–200mmol/24 h, and < 100mmol/24 h, respectively. Results: In the multivariate logistic regression models, high and medium 24h-UNa were negatively associated with achieving targets of office BP (p = 0.049 and 0.015), and morning home BP (p < 0.001 and 0.026). The eGFR was negatively associated with office BP (p = 0.021), 4 p.m. (p = 0.002) and night home BP (p = 0.012). Compared with three Anti-HD, four or more drugs’ treatment was not associated with the higher BP control rate for either office or home BP (only except 4 p.m. BP). Conclusion: High sodium intake is a negative predictor for office and morning BP target attainment, which is probably due to high-sodium related hyperresponsiveness of arteries to catecholamine. Our findings emphasize the importance of sodium restriction in the treatment of RH.

Abstract Rationale: Complete heart block (CHB) is a common clinical manifestation. Systemic sclerosis (SSc) is a rare etiology of CHB that has not received enough attention. Whether pacemaker implantation is required remains inconclusive, especially when patients have no symptoms or mild symptoms of CHB. Patient concerns: In this study, we report the case of a 48-year-old Chinese male who suffers from SSc and CHB. Diagnose: The patient was previously diagnosed with left anterior hemiblock (LAHB) and right bundle block with normal heart function. CHB was observed on a regular follow-up electrocardiogram (ECG) examination 1 month before his hospitalization. Interventions: A permanent dual chamber pacemaker was implanted. Outcomes: The patient responded well to pacemaker implantation treatment, and his exertional dyspnea disappeared. Lessons: The occurrence of heart block associated with SSc often appears concealed. The case highlights the importance of regular follow-up of a patient with SSc. Pacemaker implantation might be unavoidable if CHB is secondary to SSc, even if it is asymptomatic.

Objectives: To study the effect of high-sodium intake on functional vasodilatation of mesenteric small artery (MSA) in Dahl salt-sensitive (DS) rats. Methods: 24 8-week male DS rats were randomized into 4 groups and administrated with normal sodium (0.6% NaCl, NS group), low sodium (0.3% NaCl, LS group) and high sodium (8% NaCl, HS group) diet, and HS plus benazepril (10 mg/kg/d, HB group) treatment, respectively. MSA inner diameter recorded by GigaView high-speed camera was used to evaluate the acetylcholine (10 μg/kg, Ach)-induced vasodilatation in situ and in vivo. Full-Field Laser perfusion imaging (LPI) was taken to record video frame rate images of blood flow before and after Ach infusion. Results: After 6-week dietary intervention, compared with that in NS group, Ach-induced MSA vasodilatation in LS group increased (103.35 ± 24.46% vs. 58.26 ± 19.50%, P < 0.01), in HS group decreased (31.15 ± 17.88% vs. 58.26 ± 19.50%, P < 0.05) significantly, and was similar in HB group (57.96 ± 24.70% vs. 58.26 ± 19.50%). Meanwhile, the vasodilatation in HB group was greater than that in HS group (P < 0.05) (Fig. 1A). After Ach infusion, in comparison to NS group, MSA blood perfusion significantly increased in LS group (40.64 ± 9.00% vs 18.04 ± 10.95%, p < 0.05) and attenuated in HS group (5.62 ± 3.39% vs. 18.04 ± 10.95%, p < 0.05), with no difference in HB group (20.59 ± 10.76% vs. 18.04 ± 10.95%) (Fig. 1B). Ach-induced alteration of MSA blood perfusion was greater in HB group than that in HS group (P < 0.05). Conclusion: High sodium intake severely impaired functional vasodilatation of the small artery in DS rats, which could be ameliorated by benazepril. Our findings highlighted the significance of sodium restriction on arterial function and hypertension treatment.

Objectives: To study the associations between sodium intake and target organ damage in patients with refractory hypertension (RH). Methods: We consecutively recruited 147 RH patients (47.6% male, age 54.14 ± 16.15 years) who took at least three antihypertensive drugs including diuretics. 24-hour urinary sodium excretion (24hUNa) was measured to estimate the daily sodium intake. The left ventricular inner diameter and wall thickness were measured at end-diastole with Two-dimensionally guided M-mode echocardiography (GE vivid E9). Left ventricular mass index (LVMI) was calculated using the American Society of Echocardiography Convention. 24-hour urinary proteinuria(24hUPr) and the urinary albumin-creatinine ratio (ACR) were detected to evaluate the proteinuria, including microalbuminuria(MAlb). Logistic regression analysis was performed to determine independent risk factors related to target organ damage. The variables included in the model were: age, body mass index(BMI), current smoking, alcohol consumption, diabetes mellitus, office blood pressure (BP) and 24hUNa. Results: Logistic regression analysis showed that 24hUNa was an independent correlative factor of increased LVMI (OR 1.008, 95% CI 1.000–1.016, P = 0.039), 24hUPr (OR 1.017, 95% CI 1.004–1.029, P = 0.008) and increased ACR (OR 1.008, 95%CI 1.001–1.015, P = 0.035). The attainment of office BP target favorably affected LVMI (OR 0.136, 95% CI 0.034–0.546, P = 0.005). The analysis also revealed that diabetes mellitus was associated with abnormally increased ACR (OR 5.85, 95% CI 1.634–19.789, P = 0.006) and MAlb (OR 5.363, 95% CI 1.355–21.231, P = 0.017). Conclusion: In patients with RH, high sodium intake unfavorably affected left ventricular hypertrophy and proteinuria. Diabetes mellitus was closely related to the renal impairment.