MiR-125b and SATB1-AS1 might be shear stress-mediated therapeutic targets.

The aim of the study was to explore the potential molecular mechanism associated with shear stress on abdominal aortic aneurysm (AAA) progression. This study performed RNA sequencing on AAA patients (SQ), AAA patients after endovascular aneurysm repair (EVAR, SH), and normal controls (NC). Furthermore, we identified the differentially expressed microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNA (cirRNAs) and constructed competing endogenous RNA (ceRNA) networks. Finally, 164 differentially expressed miRNAs, 179 co-differentially expressed lncRNAs, and 440 co-differentially expressed circRNAs among the three groups were obtained. The differentially expressed miRNAs mainly enriched in 325 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Target genes associated with co-differentially expressed genes among the group of SH, SQ, and NC mainly enriched in 66 KEGG pathways. LncRNA-miRNA-mRNA interactions, including 15 lncRNAs, 63 miRNAs and 57 mRNAs, was constructed. CircRNA-miRNA-mRNA ceRNA network included 79 circRNAs, 21 miRNAs, and 49 mRNAs. Among them, KLRC2 and CSTF1, targeted by miR-125b, participated in cell-mediated immunity regulation. MiR-320-related circRNAs and SATB1-AS1 serving as the sponge of miRNAs, such as has-circ-0129245, has-circ-0138746, and has-circ-0139786, were hub genes in ceRNA network. In conclusion, AAA patients might be benefit from EVAR based on various pathways and some molecules, such as miR-125b and SATB1-AS1, related with shear stress.

lncRNA ANRIL accelerates wound healing in diabetic foot ulcers via modulating HIF1A/VEGFA signaling through interacting with FUS.

BACKGROUND: Diabetic foot ulcer (DFU) is a frequently diagnosed complication of diabetes, and remains a heathcare burden worldwide. However, the pathogenesis of DFU is still largely unclear. The objective of this study is to delineate the function and underlying mechanism of lncRNA antisense non coding RNA in the INK4 locus (ANRIL) in endothelial progenitor cells (EPCs) and DFU mice. METHODS: The DFU mouse model was established, and EPCs were subjected to high glucose (HG) treatment to mimic diabetes. qRT-PCR or western blot was employed to detected the expression of ANRIL, HIF1A, FUS and VEGFA. CCK-8 and Annexin V/PI staining were used to monitor cell proliferation and apoptosis. Wound healing, Transwell invasion and tube formation assays were conducted to assess cell migration, invasion and angiogenesis, respectively. The association between ANRIL and FUS was verified by RNA pull-down and RIP assays. Luciferase and ChIP assays were employed to investigate HIF1A-mediated transcriptional regulation of VEGFA and ANRIL. The histological alterations of DFU wound healing were observed by H&E and Masson staining. RESULTS: ANRIL was downregulated in peripheral blood samples of DFU patients, DFU mice and HG-treated EPCs. Mechanistically, ANRIL regulated HIFA mRNA stability via recruiting FUS. VEGFA and ANRIL were transcriptionally regulated by HIF1A. Functional experiments revealed that HG suppressed EPC proliferation, migration, invasion and tube formation, but promoted apoptosis via ANRIL/HIF1A axis. ANRIL accelerated DFU wound healing via modulating HIF1A expression in vivo. CONCLUSION: ANRIL accelerated wound healing in DFU via modulating HIF1A/VEGFA signaling in a FUS-dependent manner.

MiR-137 regulates low-intensity shear stress-induced human aortic endothelial cell apoptosis via JNK/AP-1 signaling.

The objective of this study is to evaluate the role of miR-137 in low-intensity shear stress-induced endoplasmic reticulum (ER) stress and cell apoptosis in human aortic endothelial cells (HAECs). HAECs were transfected with miR-137 mimic, miR-137 inhibitor, or the corresponding negative control and then exposed to pulsatile shear stress in a parallel-plate flow chamber at 1, 2, 5, 10, and 15 dyn/cm2 for 3 h. Real-time polymerase chain reaction was used to detect mRNA expression of miR-137 and SDS22. A dual-luciferase reporter assay was employed to verify the direct interaction between miR-137 and SDS22. The internal morphology of cells and cell apoptosis was assessed by TUNEL staining observed under a transmission electron microscope. Meanwhile, the protein expression of oxidative stress-related, apoptosis-related, and activated c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) signaling-related genes were analyzed by western blotting. Low strength shear stress (0-5 dyn/cm2) caused a negative change of HAEC surface and internal morphology in an intensity-dependent manner, and these changes were gradually weakened when shear stress was increased more than 5 dyn/cm2. Furthermore, low-intensity shear stress promoted oxidative stress response, accelerated cell apoptosis, and upregulated miR-137 expression and JNK/AP-1 signaling in HAECs. MiR-137 directly targets SDS22. Knockdown of miR-137 noticeably reduced activation of JNK/AP-1 signaling, oxidative stress response, and cell apoptosis induced by shear stress. MiR-137 regulated low-intensity shear stress-induced human aortic endothelial cell ER stress and cell apoptosis via JNK/AP-1 signaling.

Clusters of sudden unexplained death associated with the mushroom, Trogia venenata, in rural Yunnan Province, China.

INTRODUCTION: Since the late 1970's, time-space clusters of sudden unexplained death (SUD) in northwest Yunnan, China have alarmed the public and health authorities. From 2006-2009, we initiated enhanced surveillance for SUD to identify a cause, and we warned villagers to avoid eating unfamiliar mushrooms. METHODS: We established surveillance for SUD, defined as follows: sudden onset of serious, unexplained physical impairment followed by death in <24 hours. A mild case was onset of any illness in a member of the family or close socially related group of a SUD victim within 1 week of a SUD. We interviewed witnesses of SUD and mild case-persons to identify exposures to potentially toxic substances. We tested blood from mild cases, villagers, and for standard biochemical, enzyme, and electrolyte markers of disease. RESULTS: We identified 33 SUD, a 73% decline from 2002-2005, distributed among 21 villages of 11 counties. We found a previously undescribed mushroom, Trogia venenata, was eaten by 5 of 7 families with SUD clusters compared to 0 of 31 other control-families from the same villages. In T. venenata-exposed persons SUD was characterized by sudden loss of consciousness during normal activities. This mushroom grew nearby 75% of 61 villages that had time-space SUD clusters from 1975 to 2009 compared to 17% of 18 villages with only single SUD (p<0.001, Fisher's exact test). DISCUSSION: Epidemiologic data has implicated T. venenata as a probable cause of clusters of SUD in northwestern Yunnan Province. Warnings to villagers about eating this mushroom should continue.

[Clinical features of unexpected sudden death clustered in 7 families in Yunnan Province].

OBJECTIVE: To investigate the clinical features of unexpected sudden death (SUD) clustered in families in Yunnan province. METHODS: This retrospective study analyzed the clinical features of SUD occurred between July to September 2005 in 7 families in Yunnan province. RESULTS: All 16 SUD patients shared common clinical features such as fatigue and repeated syncope and one group of SUD patients (n = 8 from 4 families) presented with the gastric intestinal tract manifestations including nausea, vomiting, abdominal pain and diarrhea with suspected dietary history and abnormal laboratory enzyme findings (GOT/GPT, CK/CKMB, LDH/LDH1 etc.). In SUD patients without gastric intestinal tract manifestations (n = 8 from 3 families), there were no clear symptoms before death and repeated ventricular tachycardia and ventricular fibrillation were recorded in one survivor. There was no clear evidence for the involvements of hereditary and infectious factors for observed SUD. CONCLUSION: The reason for the unexpected sudden death clustered in 7 families in Yunnan remains unclear. Repeated syncope and fatigue served as the common clinical features in the presence or absence of gastric intestinal tract manifestations in all SUD cases. Further studies are needed to clarify the pathology and detailed clinical manifestations of SUD occurred in this area.

[Pathological study of unexpected sudden death clustered in family or village in Yunnan province: report of 29 cases of autopsy].

OBJECTIVE: To investigate the pathological features and causes of sudden death clustered in family or village in Yunnan province so as to provide the morphological basis for exploring its etiology and medical intervention. METHODS: Autopsy was performed on 29 cases of clustered in family or village in Yunnan province during the period 1991-2006, 16 males and 13 females, aged 32 (8-69), accounting for 10.2% of whole sudden unexpected deaths occurring in the same period. The heart, lung, liver, spleen, brain, kidney, intestinal tract, and other organs were examined macroscopically and histologically, including a study of cardiac conduction system in 5 cases. Pathological diagnosis of myocarditis was based on the Dallas Criteria and World Heart Federation's consensus while the histological evaluation of Keshan disease referred the China national guideline for pathological diagnosis of Keshan disease. RESULTS: Based on the main pathological changes and the causes of death, these cases were classified into seven groups (group A-G). Group A comprised 11 cases (38%) with lymphocytic myocarditis accompanied with focal myocardial necrosis or degeneration. Group B comprised 3 cases (10%) with neutrophil myocarditis accompanied with focal myocytolysis or coagulation necrosis. Group C comprised 4 cases (14%) with arrhythmogenic right ventricle cardiomyopathy in which fatty infiltration of myocardium was the only pathological finding. Group D comprised 2 cases (7%) with ischemic heart disease in which fresh or old foci of myocardial infarction were found but coronary stenosis was shown only in one case. Group E comprised 2 cases (7%) with left ventricle hypertrophy and obstructive muscle bundle in the outflow of left ventricle. Group F comprised 2 cases (7%) with allergic bronchitis or chronic bronchitis and pulmonary emphysema. Group G comprised the remaining 5 cases (17%) without any pathological finding that could explain sudden death. No cases suffered with Keshan disease and dilated cardiomyopathy. Focal but not diffuse inflammatory infiltration was the prominent histological feature of myocarditis in Yunnan cases. Among the five cases with histological examination of cardiac conduction system, 2 cases were detected to suffer from acute hemorrhage in His bundle and its left branching site, and the atrioventricular node of 1 case was involved. Different pathological changes coexisted in 4 pairs of family members as a cluster of sudden deaths. 3 of 4 first deaths had focal myocarditis and the other one had chronic infection. But 3 secondary deaths had myocardial ischemia and the other one had arrhythmogenic right ventricle cardiomyopathy. Pulmonary edema, acute respiratory infection and congestive or ischemic liver necrosis were found in some cases simultaneously. CONCLUSION: The pathological changes of the cases of clustered sudden death in Yunnan province are various, such as myocarditis, myocardial dysplasia and the other lethal heart-lung disorders. No case of Keshan disease has been found. Arrhythmogenic right ventricle cardiomyopathy and other foundational heart diseases might act as a background. It is very hard to contribute only one etiological factor to the clustering of sudden death in Yunnan. It was most likely that multiple factors cluster and trigger an outbreak of death in a definite time and space.

[Investigation and analysis on the incidence of "Yunnan unknown-cause sudden cardiac death" during].

OBJECTIVE: To understand the epidemiologic and clinical characteristics of the "Yunnan unknown-cause sudden cardiac death (YUSCD)". METHODS: Cases of YUSCD occurred in 2002-2004 were investigated with cross-sectional study. Clinical manifestation was observed and analyzed. RESULTS: The YUSCD areas were mountainous and most of the YUSCD cases appeared between June and August. Most of the YUSCD cases were young farmers and showed family/village clustering nature. Most of the patients died quickly with only few recovered. The overall incidence of YUSCD was 1.83% with mortality as 1.51%. The fatality rate of YUSCD appeared to be 78.1%. CONCLUSION: The YUSCD cases had a clustering feature along with time and area. The clinical manifestation of YUSCD could not be specifically identified, making the clinical diagnosis and treatment difficult when practicing in the fields that called for further studies on epidemiology, clinical work and etiology.

[Morphologic features of sudden cardiac death in Yunnan province, with emphasis on myocarditis].

OBJECTIVES: To study the pathologic feature of sudden cardiac death in Yunnan province and to investigate the role of myocarditis. METHODS: During the period from 1991 to 2006, there were 29 cases of sudden cardiac death with autopsy performed. Fourteen of these cases were diagnosed to have myocarditis based on Dallas criteria and World Heart Federation's consensus. The clinical and pathologic findings were reviewed. The cardiac conduction system was examined in details by serial sectioning in 3 cases. RESULTS: Fourteen cases suffered with myocarditis, which accounted for 48% of all cases of sudden cardiac death studied. The age of the deceased ranged from 8 to 68 years (mean = 30 years), with male-to-female ratio equaled to 9:5. Lymphocytic myocarditis and neutrophil myocarditis were the two major types, affecting 11 and 3 cases, respectively. The inflammatory infiltrates were often patchy rather than diffuse. The inflammatory foci were detected only in 8% to 42% (average = 20%) of the paraffin sections of the heart tissue. These lesions were usually located in the lateral wall of left ventricle and occasionally in interventricular septum and right ventricular wall. Myocardial injury was mild in most cases while patchy myocytolysis or coagulation necrosis was observed only in a few cases. Most of the lesions were relatively new and histologic evidence of myocardial repairing sometimes coexisted. Pericarditis and subacute endocarditis were also identified in 4 and 1 cases, respectively. Atrioventricular node was involved by myocarditis in 1 of the 3 cases examined for cardiac conduction system. Two cases showed gross evidence of cardiac dilatation (either left ventricle or biventricular). Respiratory tract and pulmonary infection was present in 5 cases. CONCLUSIONS: Myocarditis represents one of the major pathologic changes of sudden cardiac death occurring in Yunnan province. The inflammation is usually focal. Further studies are required for delineation of possible etiologies which may include virus, bacteria or exogenous toxin.

[Retrospective study on 116 unexpected sudden cardiac deaths in Yunnan, China].

OBJECTIVE: To identify the epidemiological and clinical features of unexpected sudden cardiac deaths (SUD) in Yunnan. METHODS: Choosing the old SUD cases from Xiangyun, Heqing, Nanjian and Dayao counties and using the standardized verbal autopsy Form, we interviewed the family members of the cases, witnesses and doctors as well as reviewing their medical files to get relative information. RESULTS: We identified 116 SUDs in 21 villages from 1984 to 2004. The village-specific annually standardized incidence rates were ranged from 0.2/1000 to 8.9/1000 (median = 0.8/1000). 66% and 29% of the SUDs occurred in July and August respectively. The incidence rates of SUD were higher (1.6/1000, chi(2) = 16, P < 0.01) in 10 - 39 year-olds, and higher in females than in males (RR = 1.6, 95% CI: 1.1 - 2.3). Seventy percent of SUD occurred in families having clustering nature and 60% of the additional cases in the family were occurred within 24 hours (median = 20 hours) after the first SUD identified in the family. SUD occurred in 23 families followed the first affected family in a village during the same season. In these 23 families, 61% of the first SUD occurred within 8 days after the first SUD in the first affected family. 68% and 66% of the SUDs did not have any complaints or signs during the last 3 weeks or from 3 weeks to 2 days prior to the onset of the disease. 63% of the SUDs had cardiac symptoms within the last 2 days prior to the onset with major symptoms as dizziness, nausea, faintness, unconsciousness, weakness and palpitation. The median duration from acute onset to death was 2 hours. CONCLUSIONS: The extreme time-space clustering of SUD in families and in villages suggested that the risk factors occurred in specific time and location. Familial clustered SUD cases had common exposure pattern. Sudden onset of acute cardiac symptoms often followed by sudden death. Epidemiological study on new cases was necessary to identify risk factors and to develop hypothesis for causation. In July 2005, we instituted a special SUD surveillance system for all the affected counties together with 10 counties which had no reported cases.