Associations of long-term exposure to particulate matter with gallstone risks in Chinese adults: A large cross-sectional study.

BACKGROUND: Epidemiological evidence regarding the relation of exposure to ambient particulate matter (PM) with gallstone disease (GSD) risk remains lacking. We tested the hypothesis that long-term exposure to PM is related to the development of GSD and that dyslipidemia can mediate the effect of PM-associated GSD formation. METHODS: We extracted related information on the basis of the baseline survey of the China Multi-Ethnic Cohort Study. The exposure levels of PM (PM1, PM2.5, and PM10) were assessed by validated spatiotemporal models. The relation of exposure to ambient PM with GSD risks was analyzed by non-conditional logistic regression models. Additionally, mediation analysis was conducted to assess whether dyslipidemia was related to the relation of PM exposure with GSD risks. RESULTS: A total of 72,893 participants were included. Increased ambient PM exposure was positively associated with a higher GSD risk, with ORs (and 95% CI) of 1.17 (1.06, 1.28), 1.10 (1.05, 1.15), and 1.07 (1.04, 1.10) for every 10 µg/m3 increment in PM1, PM2.5, and PM10, separately. The association was more remarkable in males, drinkers, and central obesity participants. Dyslipidemia significantly mediated the association between PM and GSD, with mediating proportions of 5.37%, 9.13%, and 7.66% in PM1, PM2.5, and PM10, respectively. CONCLUSION: Exposure to PM may relate to the increased risk of GSD in Chinese adults, especially among males, drinkers, and central obesity participants. Dyslipidemia may partially mediate the effect of PM-associated GSD development. Our results might provide epidemiological evidence for the progression of GSD related to PM and give new insights into GSD prevention and screening priorities.

Dietary Patterns and Gallstone Risks in Chinese Adults: A Cross-sectional Analysis of the China Multi-Ethnic Cohort Study.

BACKGROUND: Little is known about the association between a plant-based diet and the risk of gallstone disease (GD), especially in developing counties. We tested the hypothesis that shifting dietary patterns would be related to the risk of GD, and that the Mediterranean diet (MED) adjusted for China would be beneficial for lowering risk of GD. METHODS: Data were extracted from the baseline survey of the China Multi-Ethnic Cohort study. An alternative Mediterranean diet (aMED) score was assessed based on a food frequency questionnaire, and three posteriori dietary patterns (the modern dietary pattern, the coarse grain dietary pattern, and the rice dietary pattern) were identified using factor analysis. Multivariable logistic regression models were developed to evaluate the association between dietary patterns and GD risks. RESULTS: A total of 89,544 participants were included. The prevalence of GD was 7.5%. Comparing the highest with lowest quintiles, aMED was associated with an increased risk of GD (OR 1.13; 95% CI, 1.04-1.24; Ptrend = 0.003), whereas the rice dietary pattern was inversely related to GD risk (OR 0.79; 95% CI, 0.71-0.87; Ptrend < 0.001). In stratified analysis, the rice dietary pattern had a stronger inverse association in the subgroups of females, older, urban, and overweight participants, and those with diabetes-factors associated with higher rates of GD in previous studies. CONCLUSION: Higher adherence to the rice dietary pattern was associated with a lower risk of GD. For high-risk populations, making some shift to a traditional agricultural diet might help with primary prevention of GD.

Effects of Co-exposure to Fluoride and Arsenic on TRAF-6 Signaling and NF-κB Pathway of Bone Metabolism.

Little is known about the combined effect of fluoride (F) and arsenic (As) on bone metabolism. This study aims to explore the effect of co-exposure to F and As on the expressions of TNF receptor-associated factor 6 (TRAF-6), nuclear factor-kappa B (NF-κB), and the related factors in cell and animal experiments. With the rats exposed to different doses of F, As, and combined F-As, we found that F exposure doses were positively correlated with the protein expression of receptor activator of nuclear factor-kappa B ligand (RANKL), receptor activator of nuclear factor-kappa B (RANK), TRAF-6, NF-κB, and nuclear factor of activated T cells (NFAT-c1) (P < 0.001). As exposure doses were negatively correlated with RANK, TRAF-6, NF-κB, and NFAT-c1 (P < 0.001). The effect of F and As interaction on the protein expression of RANKL, TRAF-6, NF-κB, and NFAT-c1 was significant in bone tissue (P < 0.05). In the cellular experiment, F could promote the mRNA expression of RANK, TRAF-6, and NFAT-c1. A higher concentration of As could inhibit the mRNA expression of Tartrate-resistant acid phosphatase (TRAP), RANK, TRAF-6, and NFAT-c1. The effect of F and As interaction on the mRNA expression of TRAP, RANK, TRAF-6, and NFATc1 in osteoclasts was significant (P < 0.001). In conclusion, the expression of TRAF-6 and NF-κB pathway was affected by F and As co-exposure in osteogenic differentiation, and As could antagonize the promoting effect of F on the expression of TRAF-6, TRAP, RANKL, RANK, NF-κB, and NFAT-c1 in these exposure levels. These results could provide a scientific basis for understanding the interaction of F and As in bone formation.

The dose-response relationship of serum uric acid with Dyslipidaemia and its components: a cross-sectional study of a Chinese multi-ethnic cohort.

BACKGROUND: The association between serum uric acid (SUA) and the components of dyslipidaemia and their dose-response relationships have not been thoroughly explored. This study assessed the relationship between SUA and each dyslipidaemia component in Dong, Miao, and Bouyei populations in Guizhou by sex and ethnicities and investigated the dose-response relationship. METHODS: In total, 16,092 participants aged 30-79 years from The China Multi-Ethnic Cohort (CMEC) Study were examined. Multivariable logistic regression models were applied to explore the relationship between SUA and each dyslipidaemia component by sex and three ethnicities. The dose-response associations between SUA and various dyslipidaemias were investigated using restricted cubic spline regression. RESULTS: After controlling for confounding factors, the SUA level in total participants positively correlated with each dyslipidaemia component, and women had higher odds ratios (ORs) for each dyslipidaemia component than men (P for trend < 0.001). At the SUA level > 6.37 mg/dL, ORs (95% CI) for dyslipidaemia in the Dong, Miao and Bouyei were 2.89 (2.00-4.19), 2.43 (1.70-3.48), and 3.26 (2.23-4.78), respectively. When the SUA concentration increased by 1 mg/dL, the ORs (95% CI) for total dyslipidaemia was 1.31 (1.24-1.37). A positive dose-response but nonlinear association was found between SUA and total dyslipidaemia, high total cholesterol, and low HDL, whereas an inverse U-shaped association was found between SUA and high LDL-C ( P-nonlinear< 0.0001). CONCLUSION: The SUA level was positively correlated with each dyslipidaemia component in Dong, Miao, and Bouyei adults, and sex and ethnic differences were also found. A nonlinear dose-response relationship was found between SUA levels and dyslipidaemia and its components. Further research is warranted to investigate the causal link between SUA levels and dyslipidaemia incidence.

Hyperuricemia is Related to the Risk of Cardiovascular Diseases in Ethnic Chinese Elderly Women.

Background: The association between hyperuricemia (HUA) and cardiovascular diseases (CVDs) is not fully elucidated. Objective: To assess the relationship according to factors of sex and age in the Chinese ethnic groups. Methods: We performed a population-based cross-sectional study in a multi-ethnic population from southwestern China. HUA patients were identified by serum uric acid ≥7 mg/dL in men and 6 mg/dL in women. The outcome was composite prevalent CVDs, including coronary heart disease (CHD), stroke, and arrhythmia. Multivariate logistic regression analysis, estimating odds ratio (ORs) and 95% confidence intervals (CIs), were applied to evaluate the HUA-CVDs relationship. Results: We included 16,618 people (37.48% Dong, 30.00% Miao, and 32.52% Bouyei) aged 30-79 years without a reduced estimated glomerular filtration rate <60 mL/min/1.73 m2. CVDs developed in 250 Dong, 196 Miao, and 205 Bouyei adults. Among women, HUA was positively associated with the risk of stroke in Dong ethnicity and CVDs in Bouyei ethnicity (ORs (95% CIs) 2.02 (1.07-3.81) and 1.66 (1.06-2.59)) compared with non-HUA. In the age-specific analysis, HUA was related to the risk of CVDs (OR 2.32, 95% CI 1.00-5.38) and CHD (5.37, 1.61-17.89) among Miao people aged < median age, CVDs (1.52, 1.11-2.08) and stroke (1.67, 1.02-2.72) among Dong adults aged ≥ median age, and CVDs (1.67, 1.16-2.40) and CHD (1.77, 1.13-2.77) among Bouyei ethnicity aged ≥ median age. After stratification by sex and the median age, for women aged > 50 years, a 55% (1.55, 1.00-2.39) and 65% (1.65, 1.02-2.66) increased risk for CVDs was observed in Dong and Bouyei ethnicities. Conclusions: HUA may be related to an increased risk of CVDs among women in the Dong and Bouyei ethnic groups in China, especially women aged > 50 years.

Tolerance to Glucose and Lipid High Metabolic Reactions After Burns in an Obese Rat Model.

The goal of this study was to determine what effect obese body weight and a burn injury can have on the metabolism of glucose and lipids in rats. We used a 3 * 3 factorial model design to provide basic glucose and lipid metabolic data characterizing the interaction between different weight and burn injury groups. Two hundred Sprague Dawley rats were categorized into three weight groups (normal, overweight, obese) and then further divided into control, second-degree, and third-degree burn groups. Our model compared interactions between weight and burn injury factors according to the above groups. Blood glucose and lipid metabolism indicators were monitored on the 1st, 3rd, 7th, and 14th days after burn injury occurred, and burned skin and blood samples were collected for testing. Compared with the normal weight group, the overweight group's fast blood glucose, fast insulin, and homeostasis model assessment of insulin resistance were higher (P < .05), and FBG in the obese group was higher than the normal weight group (P < .05). Burn injuries combined with obese body weight had an interactive effect on fast blood glucose, fast insulin, and homeostasis model assessment of insulin resistance after burn injury (P < .05). Burn injury combined with obese body weight had an interaction on low-density lipoprotein cholesterol on the 3rd day after burn injury (P < .05). Burn injury combined with obese weight had no interaction on triglyceride, total cholesterol, and high-density lipoprotein cholesterol (P > .05). Rats in the overweight and obese weight groups were observed to develop an adaptation and tolerance to a higher metabolic rate after burn injuries occurred.

A multiethnic association analysis of hyperuricaemia with cardiovascular risk in rural and urban areas in Chinese adults.

Comprehensive research on rural-urban disparities in the association of hyperuricaemia (HUA) with cardiovascular disease (CVD) in China, especially among minority groups, is limited. We explored the HUA-CVD relationship between rural and urban areas within ethnic Chinese groups. We included Dong, Miao, and Bouyei adults in Southwest China from the China Multi-Ethnic Cohort Study. Multivariable logistic regression models were used to assess the relationship between HUA and CVD in both residences. We performed stratified analyses by sex and age. The study population included 16,618 people (37.48% Dong, 30.00% Miao, and 32.52% Bouyei) without a reduced estimated glomerular filtration rate. We identified 476 (188 Dong, 119 Miao, and 169 Bouyei) and 175 (62 Dong, 77 Miao, and 36 Bouyei) CVD cases in rural and urban areas. Compared to urban residents, an at least 49% increased CVD risk (adjusted OR 1.49, 95%CI 1.06-2.08 for the Dong ethnic group; 1.55, 1.07-2.25 for the Bouyei ethnic group) and a 1.65-fold elevated coronary heart disease risk (1.65, 1.03-2.64) related to HUA was present in rural residents. Moreover, HUA was positively associated with increased risk of CVD and coronary heart disease in rural women (2.05, 1.26-3.31; 2.11, 1.19-3.75) and rural older adults (1.83, 1.22-2.75; 2.32, 1.39-3.87) among the Bouyei ethnic group, respectively. We found rural elderly individuals with HUA among the Dong ethnic group had a 52% elevated risk of CVD (1.52, 1.05-2.21); furthermore, an at least 79% increased risk of stroke related to HUA was observed in women (2.24, 1.09-4.62) and elderly people (1.79, 1.02-3.13) in rural areas among the Dong ethnic group. But a positive association was not found among the Miao ethnic group. Screening early-onset HUA patients may be helpful for the control and prevention of CVD in rural residents, especially for women and older adults living in a rural community, among the Dong and Bouyei ethnic groups in China.

Characteristic and Introspection of Road Traffic Injuries in China from 2012 to 2017.

BACKGROUND: To analyze whether the area differences of RTIs (road traffic injuries, RTIs) caused by unequal development in China, provide suggestions for the prevention of the RTIs. METHODS: The data of RTIs in China was collected from the authoritative official website and yearbook of China. RESULTS: Total RTIs in the East was the highest (RTIs frequency: 591789; injured people: 600611; death toll: 168885; economic loss: 27.22 billion RMB), followed by the Center (RTIs frequency: 321807; injured people: 352769; death toll: 91966; economic loss: 23.90 billion RMB) and the lowest in the West (RTIs frequency: 289482; injured people: 332517; death toll: 101095; economic loss: 16.35 billion RMB). The multivariate linear correlation and regression showed that the characteristic of RTIs was highly related with GDP (r=0.99, P < 0.001). CONCLUSION: The economically developed areas had a large amount of traffic damages. The government should focus on preventing high RTIs in the East and high death tolls in the West.

Pro-inflammatory effect of obesity on rats with burn wounds.

OBJECTIVE: A burn is an inflammatory injury to the skin or other tissue due to contact with thermal, radioactive, electric, or chemical agents. Burn injury is an important cause of disability and death worldwide. Obesity is a significant public health problem, often causing underlying systemic inflammation. Studying the combined impact of burn injuries on obese patients has become critical to the successful treatment of these patients. The aim of this paper is to highlight the effect of inflammation associated with burn injuries on several body weight group in a rat study. MATERIALS AND METHODS: Different degrees of obesity and burns were established in rats and divided into a normal weight group, overweight group, obese group, second-degree burn group, third-degree burn group, over-weight second-degree burn group, over-weight third-degree burn group, obese second-degree burn group, and obese third-degree burn group (20 rats per group). Changes in inflammatory factors and growth factor were measured on the 1st, 3rd, 7th and 14th days after burns were inflicted. RESULTS: The ELISA test showed that in the unburned control group, MCP-1, IL-1ß and TNF-α protein expressions in the obese and over-weight groups were higher than the normal-weight group (P < 0.05). RT-PCR test showed that the expressions of MCP-1, IL-1ß and TNF-α genes in the obese group were higher compared to the overweight and normal weight groups (P < 0.05). Three and 7 days after burns were inflicted, the level of VEGF in the normal weight group was higher than the obese group (P < 0.05), however increased VEGF was not observed on days 1 and 14. CONCLUSION: Burn injury and obesity have a mutually synergistic effect on the body's inflammatory response.

Suicides in China from 2008-2017: A longitudinal epidemological study.

INTRODUCTION: We aimed to describe the change of suicide rates in China from 2008 to 2017 and provide suggestions for the prevention of suicide. SUBJECTS AND METHODS: A longitudinal study included the time point tracking were used in our study. The suicide data in China were collected from the authoritative official website and yearbook of China from 2008 to 2017. Data were analyzed by SPSS (version 18.0, IBM Corp., Armonk, NY, USA). Origin (version 9.0) was used for graph. RESULTS: We found that the suicide rate in China showed a downward trend. The suicide rate for males in rural was the highest, followed by rural women. Then urban male, and urban female suicide rate was the lowest. The difference was statistically significant (F = 88.35, P < 0.01). CONCLUSIONS: The suicide rate in rural areas was higher than that in cities, and men were higher than women. The government should focus on preventing high suicide rates in rural areas, especially men.

Epidemiological Characteristics and Risk Factors of Posttraumatic Stress Disorder in Chinese Children After Exposure to an Injury.

OBJECTIVE: The aim of this study is to describe the risk factors of injured children's posttraumatic stress disorder (PTSD) in China and provide the scientific data for PTSD prevention and control in children. METHODS: Electronic databases, including Medline, Science Direct, Google Scholar, and CNKI (China National Knowledge Infrastructure), were searched for articles published on or before October 30, 2018, searching for the words, "PTSD," "child"/"children," "injury"/"injuries," and "China"/"Chinese." Forty-seven articles met the inclusion criteria and were meta-analyzed using random-effect models. RESULTS: The total sample size in our meta-analysis was 65 298, and there were 13 402 children diagnosed with PTSD. The prevalence of PTSD after suffering from injury was 20.52% (95% CI = 17%-23%). PTSD occurrence was higher in girls than boys (24.61% vs 19.36%, P < 0.001). The PTSD rate for students was 51.82%, 37.12%, and 14.02% in senior, junior high school children, and primary school student, respectively. PTSD prevalence was 58.93% in rural children and higher than the urban children (57.36%). The prevalence of PTSD in ethnic minority children was significantly higher than that of Han Chinese children (35.38% vs 13.50%). CONCLUSION: PTSD in injured children is significantly higher in girls, senior high school children, in rural areas, and in ethnic minority children. PTSD prevention and control should be focused on these 4 subgroups.

Road traffic injuries in China from 2007 to 2016: the epidemiological characteristics, trends and influencing factors.

BACKGROUND: Road traffic accidents are one of the serious disasters that cause public injury, fatality and great economic loss. They are a growing public health problem around the world. OBJECTIVES: The aim of this study was to determine epidemiological characteristics, tendency and possible influencing factors of road traffic injuries (RTIs) in China, so as to give target suggestions on preventative measures. METHODS: Road traffic accident data were obtained from National Bureau of Statistics of China and Ministry of Transport of the People's Republic of China. Descriptive statistic such as RTIs frequency, trends of different accident types from 2007 to 2016; the RTIs difference between different regions and road surfaces were compared; and the possible influencing factors of RTIs were also explored. RESULTS: Over the past decade, with the mileage of constructed highway increased, the frequency of road traffic accidents have declined substantially in China, and the death toll from road traffic accidents with motor vehicles has declined from 2007 to 2015, Conversely, the number of deaths from non-motor vehicle accidents has risen rapidly since 2012. Our study showed that the traffic accident related mortality in Guizhou province was different from the level of the whole nation, and the Eastern, Central and Western areas of China were all significantly different (P < 0.001). Linear regression suggested a significant affected of gross domestic product (GDP)-per-capita, education level, the number of health institutions, populations, and car ownership status on traffic accident death tolls (P < 0.001). Moreover, cement concrete pavement roads were associated with the highest occurrence rates of RTI, and RTIs was statistically significant (P < 0.001) on different road surfaces. CONCLUSION: Even though the frequency of road traffic accidents has declined, RTIs remain an urgent public health problem in China. Thus, the government should give some target preventative measures to reduce RTIs, aiming at different regions, the increasing trend of the death toll related to non-motor vehicles and the highest occurrence on cement concrete pavement roads.

The blood parameters and liver function changed inconsistently among children between burns and traumatic injuries.

OBJECTIVE: Burn and traumatic injury are two kinds of injury by modality. They cause acute phase response and lead to a series of pathological and physiological changes. In this study, we explored whether there are differences in routine blood parameters and liver enzyme levels between burned and traumatically injured children. METHODS: Patients under 18 years old with injuries were recruited. Their demographic and clinical data were recorded. Collected clinical data included routine blood parameters (white blood cell count (WBC), red blood cell count (RBC), platelets (PLT), hemoglobin (HB)), serological enzyme levels (alanine aminotransferase (ALT), aspartate transaminase (AST), glutamyltransferase (GGT), alkaline phosphatase (ALP), cholinesterase (CHE)), and total protein (TP) levels (albumin (ALB), globulin (GLB)). A generalized linear model and multivariate analysis of variance were used to conduct comparisons. RESULTS: A total of 162 children (109 with burns and 53 with traumatic injuries) with a mean age of 4.36 ± 4.29 years were enrolled in the study. Burned children had higher levels of RBC, HB, WBC, AST and lower levels of TP, CHE, ALB than traumatically injured children (P < 0.05). Moreover, the concentration of WBC and HB was higher in males compared to females (P < 0.001). Conversely, the level of AST and TP in males was lower, AST levels were significantly lower in males (P = 0.005). Age positively correlated with the levels of HB, AST and TP (P < 0.001), and negatively correlated with WBC (P < 0.001). With decreasing body mass index (BMI), the levels of WBC, HB, AST and TP significantly increased in both groups of injured children (P < 0.001). In addition, ISS was positively correlated with WBC and HB levels (P < 0.001), but negatively correlated with AST and TP levels (P < 0.001). CONCLUSIONS: Children with burn injuries suffered a greater acute response and liver damage than traumatically injured children. This may in part underlie clinical observations of differences in children morbidity and mortality in response to different injury types.

Epidemiological characteristics and factors affecting length of hospital stay for children and adults with burns in Zunyi, China: a retrospective study.

OBJECTIVE: Burn wounds are a global public health problem, and a large number of casualties are caused by burns each year. In this study, we explored the epidemiological characteristics associated with burns and the factors affecting the length of hospital stay (LOS) in children and adults with burn wounds. METHODS: Records of patients with burns in the Affiliated Hospital of Zunyi Medical University from January 1, 2014 to August 31, 2016 were retrieved. Information on demographic characteristics, mechanism of burns, first treatment received, clinical details of burns, and LOS were extracted from hospital medical records. RESULTS: A total of 465 children and 327 adults with burns were identified over about 2.5 years. The ratio of male to female children with burn wounds was 1.6 and 2.3 in adults. The epidemiological characteristics of burns, including gender, season, location, etiology, degree and site, differed between children and adults. There were differences in external remedies used (e.g., traditional Chinese medicine powder) and wound protection (towels covering wounds) between children and adults, but few patients had both protected wounds and did not use external remedies. LOS was reduced with age (hazard ratio [HR] = 0.993) and skin grafting (HR = 0.339). LOS increased with the male gender (HR = 1.234), deep partial thickness burns (HR = 3.128), and full-thickness burns (HR = 1.791). LOS was increased when total body surface area (TBSA) of burns reached from 10% to 29% (HR = 3.978), when TBSA was greater than 30% (HR = 1.787), and heat vs. non-heat etiologies (HR = 1.497). CONCLUSION: Our findings for the epidemiological characteristics of burns in children and adults in Zunyi will help with a targeted awareness campaign and improve knowledge of first-aid and wound treatment.

Epidemiologic features and intervention effect of fall injury among rural school-aged children in southwest China: a short-term cohort study.

Falls are the top one type in all unintentional injuries. In this study, we aim to explore the epidemiological characteristics of falls and assess the intervention effect. Our research had interviewed 2854 rural children in southwest China. Then, we used School-Family-Individual (SFI) comprehensive education model to conduct an intervention among 1506 children and follow up them for one year. The changes in injury knowledge and incidence rate before and after intervention were compared. We found the fall injury was 37.32% (178/477) and ranked top one in the total injuries. After intervention, the children's fall-injuries-related knowledge was significantly increased by 15.29 percent (P < 0.001). While falls incidence significantly decreased after- intervention (6.24% vs. 3.93%; P < 0.001). From the results we concluded that the falls rate was high and was the prior reason of all injuries. SFI intervention model can effectively reduce the incidence of the fall injury.

Regulatory crosstalk between KLF5, miR-29a and Fbw7/CDC4 cooperatively promotes atherosclerotic development.

Atherogenesis is a chronic inflammatory process that involves complex interactions between endothelial dysfunction, lipid deposition and vascular smooth-muscle cell (VSMC) proliferation. However, the molecular mechanism is still unclear. We found that a pro-atherosclerotic factor (oxLDL) induced the expression of Krüppel-like factor 5 (KLF5), which in turn increased miR-29a expression levels. The increased miR-29a was retained within HASMCs and down-regulated Fbw7/CDC4 expression by targeting the 3´UTR of Fbw7/CDC4, subsequently increasing KLF5 stability by reducing the Fbw7/CDC4-dependent ubiquitination of KLF5, forming a positive feedback loop to enhance VSMC proliferation and promote atherogenesis. These results indicate a potentially important role for the oxLDL-activated feedback mechanism in VSMC proliferation and atherogenesis. Suppression of miR-29a may be an effective way to attenuate atherosclerosis. In conclusion, our data are the first to reveal that the regulatory crosstalk between KLF5, miR-29a, and Fbw7/CDC4 cooperatively promotes atherosclerotic development.

miR-29a regulates vascular neointimal hyperplasia by targeting YY1.

OBJECTIVES: The formation of vascular neointima is mainly related to impairment of the vascular endothelial barrier and abnormal proliferation and migration of smooth muscle cells. The objective of this study was to investigate whether miR-29a exerts any promoting effect on the vascular neointimal hyperplasia and if so, its mechanism. MATERIALS AND METHODS: RT-qPCR was performed to determine expression of miR-29a in vascular smooth muscle cells (VSMC) and vascular neointimal hyperplasia. To further understand its role, we restored its expression in VSMCs by transfection with miR-29a mimics or inhibitors. Effects of miR-29a on cell proliferation were also determined. RESULTS: In this study, we used two kinds of model to observe the role of miR-29a in neointimal hyperplasia induced by carotid ligation or balloon injury. The major findings were that: (i) miR-29a overexpression promoted neointimal hyperplasia induced by carotid ligation; (ii) miR-29a increased proliferation of VSMCs, one aspect of which was by targeting expression of Ying and yang 1 protein (YY1), a negative regulator of Cyclin D1. A further aspect, was by increasing expression of Krüppel-like factor 5, a positive regulator of Cyclin D1, thereby allowing formation a synergistic effect. (iii) Tongxinluo (TXL), a traditional Chinese medicine reduced neointimal formation in ligated vessels by inhibiting VSMC proliferation and migration. CONCLUSIONS: These findings provide a new molecular mechanism of TXL in decreasing neointima hyperplasia.

SUMOylation of KLF4 acts as a switch in transcriptional programs that control VSMC proliferation.

The regulation of vascular smooth muscle cell (VSMC) proliferation is an important issue due to its major implications for the prevention of pathological vascular conditions. The objective of this work was to assess the function of small ubiquitin-like modifier (SUMO)ylated Krϋppel-like transcription factor 4 (KLF4) in the regulation of VSMC proliferation in cultured cells and in animal models with balloon injury. We found that under basal conditions, binding of non-SUMOylated KLF4 to p300 activated p21 (p21(WAF1/CIP1))transcription, leading to VSMC growth arrest. PDGF-BB promoted the interaction between Ubc9 and KLF4 and the SUMOylation of KLF4, which in turn recruited transcriptional corepressors to the p21 promoter. The reduction in p21 enhanced VSMC proliferation. Additionally, the SUMOylated KLF4 did not affect the expression of KLF4, thereby forming a positive feedback loop enhancing cell proliferation. These results demonstrated that SUMOylated KLF4 plays an important role in cell proliferation by reversing the transactivation action of KLF4 on p21 induced with PDGF-BB.

miR-200c-SUMOylated KLF4 feedback loop acts as a switch in transcriptional programs that control VSMC proliferation.

The regulation of vascular smooth muscle cell (VSMC) proliferation is an important issue because it has major implications for the prevention of pathological vascular conditions. Using microRNA array screen, we found the expression levels of 200 unique miRNAs in hyperplasic tissues. Among them, miR-200c expression substantially was down-regulated. The objective of this work was to assess the function of miR-200c and SUMOylated Krϋppel-like transcription factor 4 (KLF4) in the regulation of VSMC proliferation in both cultured cells and animal models of balloon injury. Under basal conditions, we found that miR-200c inhibited the expression of KLF4 and the SUMO-conjugating enzyme Ubc9. Upon PDGF-BB treatment, Ubc9 interacted with and promoted the SUMOylation of KLF4, which allowed the recruitment of transcriptional corepressors (e.g., nuclear receptor corepressor (NCoR) and HDAC2) to the miR-200c promoter. The reduction in miR-200c levels led to increased target gene expression (e.g., Ubc9 and KLF4), which further repressed miR-200c levels and accelerated VSMC proliferation. These results demonstrate that induction of a miR-200c-SUMOylated KLF4 feedback loop is a significant aspect of the PDGF-BB proliferative response in VSMCs and that targeting Ubc9 represents a novel approach for the prevention of restenosis.