LncRNA NEAT1 aggravates human microvascular endothelial cell injury by inhibiting the Apelin/Nrf2/HO-1 signalling pathway in type 2 diabetes mellitus with obstructive sleep apnoea.

Long noncoding RNAs (lncRNAs) regulate the progression of type 2 diabetes mellitus complicated with obstructive sleep apnoea (T2DM-OSA). However, the role of the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in T2DM-OSA remains unknown. This study aimed to reveal the function of NEAT1 in T2DM-OSA and the underlying mechanism. KKAy mice were exposed to intermittent hypoxia (IH) or intermittent normoxia to generate a T2DM-OSA mouse model. HMEC-1 cells were treated with high glucose (HG) and IH to construct a T2DM-OSA cell model. RNA expression was detected by qRT-PCR. The protein expression of Apelin, NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1), and up-frameshift suppressor 1 (UPF1) was assessed using western blot. Cell injury was evaluated using flow cytometry, enzyme-linked immunosorbent assay, and oxidative stress kit assays. RIP, RNA pull-down, and actinomycin D assays were performed to determine the associations between NEAT1, UPF1, and Apelin. NEAT1 expression was upregulated in the aortic vascular tissues of mice with T2DM exposed to IH and HMEC-1 cells stimulated with HG and IH, whereas Apelin expression was downregulated. The absence of NEAT1 protected HMEC-1 cells from HG- and IH-induced damage. Furthermore, NEAT1 destabilized Apelin mRNA by recruiting UPF1. Apelin overexpression decreased HG- and IH-induced injury to HMEC-1 cells by activating the Nrf2/HO-1 pathway. Moreover, NEAT1 knockdown reduced HG- and IH-induced injury to HMEC-1 cells through Apelin. NEAT1 silencing reduced HMEC-1 cell injury through the Apelin/Nrf2/HO-1 signalling pathway in T2DM-OSA.Abbreviations: LncRNAs, long non-coding RNAs; T2DM, type 2 diabetes mellitus; OSA, obstructive sleep apnoea; NEAT1, nuclear paraspeckle assembly transcript 1; IH, intermittent hypoxia; HMEC-1, human microvascular endothelial cells; HG, high glucose; Nrf2, NF-E2-related factor 2; UPF1, up-frameshift suppressor 1; HO-1, haem oxygenase-1; qRT-PCR, quantitative real-time polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; TNF-α, tumour necrosis factor-α; CCK-8, Cell Counting Kit-8; IL-1ß, interleukin-1ß; ROS, reactive oxygen species; MDA, malondialdehyde; SOD, superoxide dismutase; RIP, RNA immunoprecipitation; SD, standard deviations; GSH, glutathione; AIS, acute ischaemic stroke; HMGB1, high mobility group box-1 protein; TLR4, toll-like receptor 4.

Differences in clinical features of hypertrophic cardiomyopathy with or without left ventricular enlargement.

BACKGROUND: Few studies have focused on the clinical features of hypertrophic cardiomyopathy (HCM) with enlarged left ventricle (ELV). METHODS: In this study, participants were patients with HCM (n=170), who were divided into two groups [ELV and normal left ventricle (NLV)] according to left ventricle size. Age at diagnosis, sex, complications, electrocardiogram (ECG), symptoms, drug treatment, and echocardiographic parameters were compared between the NLV (n=153) and ELV (n=17) groups. RESULTS: The incidence of end-stage HCM (ES-HCM) among all HCM patients was 5.29%, while that of ELV was 10.0%. For all patients with HCM and those with asymmetric septal HCM (ASHCM), there were more males with ELV than NLV. Of the patients with HCM and ASHCM, left ventricular ejection fraction (LVEF) was significantly lower in the ELV group than the NLV group; accordingly, the rates of diuretics use in the ELV group were higher than those in the NLV group. Among apical HCM (ApHCM) patients, the left atrial diameter (LAd), incidence of atrial fibrillation (Af) or ST-T change, and rate of angiotensin converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use were all higher in the ELV group compared to the NLV group. CONCLUSIONS: These findings suggest that the prevalence of ES-HCM in HCM patients with ELV was higher than those with NLV. Additionally, ELV is more common in men than women and there are differences in the clinical features of different types of HCM with ELV.

Repeated chest tightness-A case of double-chambered left ventricle in an adult.

Double-chambered left ventricle (DCLV) is a rare congenital heart disease. A hypertrophic muscle bundle in the left ventricle may cause varying degrees of obstruction in the middle of the left ventricle, resulting in different clinical symptoms. Here, we report a patient with a history of repeated chest tightness who was misdiagnosed with coronary heart disease and ventricular aneurysm. After repeated ultrasound examinations, the patient was eventually diagnosed with DCLV, which was confirmed by magnetic resonance imaging and coronary angiography. This case highlights the necessity to improve the accuracy of DCLV diagnosis via echocardiogram.

In vitro investigation of protective mechanisms of triptolide against coronary heart disease by regulating miR-24-3p-BCL2L11 axis and PPARs-PGC1α pathway.

Coronary heart disease (CHD) is a fatal disease associated with coronary atherosclerosis. Although triptolide (TTL) has been reported to protect against CHD, the mechanism has not yet been determined. This study intended to explore its molecular regulation mechanism in CHD. It is shown in this study that TTL contributed to the proliferation and migration of in vitro cell models of CHD (endothelial cells) and the inhibition of apoptosis, and had an improvement effect on apoptosis factors and endoplasmic reticulum stress (ERS). From its mechanisms, TTL evidently downregulates miR-24-3p which is elevated in CHD, and evidently upregulates BCL2-like 11 (BCL2L11) which is suppressed in CHD, as well as affects the activation of peroxisome proliferator-activated receptors (PPARs)-Peroxisome proliferator activated receptor-γ co-activator-1α (PGC-1α) pathway of nuclear receptor transcription factors. In addition, miR-24-3p-BCL2L11-PPARs-PGC1α axis regulates protective effects of TTL against CHD.

Isorhamnetin protects against bleomycin-induced pulmonary fibrosis by inhibiting endoplasmic reticulum stress and epithelial-mesenchymal transition.

The present study aimed to determine whether isorhamnetin (Isor), a natural antioxidant polyphenol, has antifibrotic effects in a murine model of bleomycin­induced pulmonary fibrosis. A C57 mouse model of pulmonary fibrosis was established by intraperitoneal injection of a single dose of bleomycin (3.5 U/kg), and then Isor (10 and 30 mg/kg) was administered intragastrically. The level of fibrosis was assessed by hematoxylin and eosin and Sirius red staining. α­smooth muscle actin and type I collagen levels in lung tissues were determined by western blotting and immunohistochemistry (IHC). Epithelial­mesenchymal transition (EMT), endoplasmic reticulum stress (ERS) and related signaling pathways were examined by western blotting and IHC. In vitro, human bronchial epithelial cells (HBECs) and A549 cells were treated with transforming growth factor (TGF)ß1 with or without Isor, and collagen deposition and the expression levels of EMT­ and ERS­related genes or proteins were analyzed by reverse transcription­quantitative polymerase chain reaction, western blotting, and immunofluorescence. The results demonstrated that Isor inhibited bleomycin­induced collagen deposition, reduced type I collagen and α­SMA expression, and alleviated EMT and ERS in vivo. Furthermore, incubation of HBECs and A549 cells with TGFß1 activated EMT and ERS, and this effect was reversed by Isor. In conclusion, Isor treatment attenuated bleomycin­induced EMT and pulmonary fibrosis and suppressed bleomycin­induced ERS and the activation of PERK signaling.

The effect of hypertension on cardiac structure and function in different types of hypertrophic cardiomyopathy: A single-center retrospective study.

OBJECTIVES: To determine whether hypertension (HTN) affects cardiac structure and function in different types of hypertrophic cardiomyopathy (HCM). DESIGN: Patients with obstructive HCM (n = 40), septal HCM (n = 88), and apical HCM (n = 42) were separated into hypertensive and non-hypertensive subgroups, and echocardiographic parameters at baseline and at follow-up were compared between the subgroups. RESULTS: At follow-up, hypertensive obstructive HCM patients showed a decrease in end-diastolic volume (from 93.87 ± 26.08 mL to 79.06 ± 20.07 mL; p= 0.045) and in left ventricular end-diastolic diameter (from 45.00 ± 5.32 mm to 41.83 ± 4.58 mm; p =0.042). Non-hypertensive obstructive HCM patients showed a decrease in maximum aortic velocity (from 2.01 ± 0.53 m/s to 1.28 ± 0.25 m/s; p= 0.011) and in aortic maximum pressure gradient (from 17.22 ± 9.57 mm Hg to 6.79 ± 2.44 mm Hg; p= 0.03). Hypertensive apical HCM patients showed an increase in end-diastolic volume (from 95.28 ± 16.54 mL to 119.74 ± 25.19 mL; p= 0.016) and in left ventricular end-diastolic diameter (from 45.28 ± 3.36 mm to 50.20 ± 4.56 mm; p= 0.007). CONCLUSIONS: HTN can affect left ventricular capacity in obstructive HCM and apical HCM, causing a decrease in ventricular capacity in the former and increase in the latter; it has no significant effect on the size of the left ventricular cavity in septal HCM. HTN can lead to a poor therapeutic effect on aortic flow rate and pressure gradient in obstructive HCM patients.

Synergistic Effect of Atorvastatin and Folic Acid on Cardiac Function and Ventricular Remodeling in Chronic Heart Failure Patients with Hyperhomocysteinemia.

BACKGROUND At present, a constant progress in pathophysiology understanding and treatment of the chronic heart failure (CHF) is arising. Meanwhile, hyperhomocysteinemia (HHcy) has been linked to impaired left ventricular function and clinical class in patients with CHF. Atorvastatin therapy can reduce the incidence of sudden cardiac death in patients with advanced CHF. Folic acid could enhance endothelial function in vascular disease states. The present study aims to investigate the effect of atorvastatin and folic acid combined on the cardiac function and ventricular remodeling in CHF patients with HHcy. MATERIAL AND METHODS Elderly CHF patients with HHcy were divided into four groups: routine, routine + atorvastatin, routine + folic acid, and routine + atorvastatin + folic acid groups. Serum homocysteine (Hcy) level was detected using enzymatic cycling methods, and N-terminal pro brain natriuretic peptide (NT-proBNP) level by ELISA. The cardiac function indexes and left ventricular early diastolic peak flow velocity/atrial systolic peak flow velocity (E/A) ratio were evaluated. The six-minute walk test was performed to measure the six-minute walk distance (6MWD). RESULTS 6MWD increased, the serum Hcy and NT-proBNP levels decreased, and cardiac function was improved compared with before treatment, which was the most significant in the routine + atorvastatin + folic acid group, followed by the routine + atorvastatin group, then the routine + folic acid group, and lastly, the routine group. CONCLUSIONS The results indicated that the combination of atorvastatin and folic acid improved the cardiac function and inhibited ventricular remodeling of elderly CHF patients with HHcy.

GAS5 knockdown reduces the chemo-sensitivity of non-small cell lung cancer (NSCLC) cell to cisplatin (DDP) through regulating miR-21/PTEN axis.

Non-small cell lung cancer (NSCLC), known as the most common type of lung cancer, has caused great economic losses and brought the patients with NSCLC great suffering. The NSCLC chemo-resistance to cisplatin (DDP) -based chemotherapy remains a huge challenge. The lncRNA growth arrest-specific 5 (GAS5) has been reported to be related with cancers including NSCLC. Phosphatase and tensin homolog (PTEN) has been frequently reported to affect chemo-sensitivity of cancers, and usually acts as a tumor suppressor. In this paper, we demonstrated a significant low GAS5expression in NSCLC patients was correlated with poorer clinicopathologic features; GAS5 knockdown by si-GAS5 transfection promoted NSCLC cell viability. Additionally, GAS5 was involved in the regulation of chemo-sensitivity of the NSCLC cell to DDP through regulation of PTEN pathway. LncRNAs commonly exerts their functions through the interaction with miRNAs. According to previous studies, miR-21 acts as an oncogenic miRNA through targeting PTEN in many cancers. In the present study, GAS5 could compete with PTEN for miR-21 binding. We further verified that the interaction between GAS5 and miR-21 was required in the regulation of NSCLC chemo-sensitivity to DDP through PTEN pathway. Taken together, the data of the present study demonstrated a novel mechanism by which GAS5/miR-21/PTEN affects the sensitivity of NSCLC to DDP-based therapy.

Aspirin inhibits fractalkine expression in atherosclerotic plaques and reduces atherosclerosis in ApoE gene knockout mice.

OBJECTIVE: To determine the fractalkine expression in the aorta of ApoE (-/-) mice and the effect of high-dose aspirin intervention on fractalkine expression and atherosclerotic lesion formation. METHODS: Twenty-one male ApoE gene knockout mice were randomized into three groups to receive either placebo in addition to normal mice chow (n = 7), placebo in addition to a high-fat diet (n = 7), or aspirin (58 mg/kg/d) in addition to a high-fat diet (n = 7). After 12 weeks of study, the mice were euthanized and serum cholesterol, thromboxane B(2), and 6-keto-PGF(1alpha) were examined. Fractalkine and cyclooxygenase expression in aorta were measured and the atherosclerotic lesion analyzed. RESULTS: Pathology image analysis showed that the atherosclerotic plaque was the most extensive in the high-fat diet group while the addition of aspirin greatly reduced the severity of the plaque. Both RT-PCR analysis and immunohistochemical analysis showed that fractalkine expression was the strongest in the high-fat diet group and was significantly decreased by aspirin treatment. Serum thromboxane B(2) was lowered by aspirin while 6-keto-PGF(1alpha) and cholesterol remained unchanged. CONCLUSIONS: The results of our study indicate that high dose aspirin can improve the atherosclerotic lesion and suppress the fractalkine expression in murine aorta.

Gender differences in autonomic modulation of ventricular repolarization in humans.

BACKGROUND: Gender differences in the incidence of ventricular arrhythmias have been reported and torsades de pointes associated with long QT syndrome are more common in women than men. Although increased sympathetic tone has an important role in vulnerability to arrhythmia, little is currently known regarding gender differences in the dynamic electrophysiological response to sympathetic stimulation. Therefore, we investigated whether there is a gender difference in humans with respect to the dynamic response of ventricular repolarization to beta-adrenergic stimulation and to autonomic blockade. METHODS: Twelve-lead ECGs were continuously recorded during isoproterenol infusion (protocol 1) and autonomic blockade with propranolol and atropine infusion (protocol 2) in 24 healthy volunteers (12 men, 23 +/- 2 years; 12 women, 23 +/- 5 years). QT (QTc) intervals were measured at the baseline and at a heart rate of 75, 100, and 120 beats/min. RESULTS: (1) The morphology of the T wave dynamically and transiently changed to bifid or biphasic during the acute phase of isoproterenol infusion. The incidence of these morphologic changes was higher in women than men (P < 0.05). (2) The QTc interval was initially prolonged and then shortened in both men and women during isoproterenol administration. However, QTc prolongation was significantly greater in women (0.44 +/- 0.02 to 0.55 +/- 0.03 sec) than men (0.42 +/- 0.03 to 0.51 +/- 0.04 sec; P < 0.05). (3) The QTc interval was significantly prolonged under autonomic blockade and the intrinsic QTc interval was longer in women than men (P < 0.05). CONCLUSION: While sympathetic stimulation and autonomic blockade modulated the dynamics of ventricular repolarization in both sexes, it was more pronounced in women. This gender difference may partially account for the susceptibility of women to arrhythmogenesis.

Heterogeneous expression of connexin 43 in the myocardium of rabbit right ventricular outflow tract.

The right ventricular outflow tract (RVOT) has been demonstrated as an important focus in idiopathic ventricular arrhythmias. However, the role of the gap junction in this region in arrhythmic events has not been fully investigated. The purpose of this study was to evaluate the expression and distribution of the gap junction protein connexin 43 (Cx43) in the myocardium of the RVOT area of normal adult rabbits. Tissue samples were obtained from 6 regions of normal rabbit heart, i.e. the left ventricle (LV) free wall, the LV papillary muscle, the RVOT free wall, and the RVOT septum which was subdivided into the RV side, the central layer, and the LV side. Immunohistochemical analysis was performed to investigate the characteristics of Cx43 distribution in the RVOT area. In the LV free wall and papillary muscle, Cx43 was abundantly, homogeneously, and approximately equally expressed in end-to-end- and side-to-side intercellular connections. In the free wall of the RVOT, Cx43 expression was poor compared to both these LV regions and side-to-side cell connections were predominant. Cx43 was as richly and homogeneously distributed in the central layer and LV side of the RVOT septum as in the two LV regions. However, in the RV side of the RVOT septum, its distribution was scant and an unstained area was noted. The heterogeneous expression of Cx43 in the RVOT area may serve as substrate for idiopathic ventricular arrhythmia.

Gender differences in the dynamics of terminal T wave intervals.

This study was designed to investigate gender differences in the dynamic changes of the terminal T wave (Ta-e interval) of healthy subjects. Holter ECGs were recorded in 24 healthy volunteers (12 men aged 23 +/- 2 years). The intervals from QRS onset to the apex (QaT) and to the end of the T wave (QeT), and the interval between the apex and the end of the T wave (Ta-e) were measured. Then, the QeT/RR, QaT/RR, and Ta-e/RR relationship was evaluated by linear regression analysis in each subject. The QeT and QaT intervals were significantly longer in women than men and the slope of the QeT/RR and QaT/RR relationship was steeper in women than men. The Ta-e intervals showed a significant but weaker positive correlation with the preceding RR intervals in 7 (58.3%) men and 9 (75.0%) women. The average values of the slope and the correlation coefficient of the Ta-e/RR relationship were significantly smaller compared to those of QeT and QaT in both men and women (P < 0.0001). The slope of the Ta-e/RR relationship was significantly greater in women than men (0.025 +/- 0.009 vs 0.011 +/- 0.012, P < 0.005). However, the Ta-e intervals were significantly longer over the entire range of RR intervals in men than women (P < 0.0001). The rate-correcting formulas of Bazett and Framingham overcorrected the Ta-e intervals. The observed gender difference in the measurement and dynamics of the Ta-e interval may help to understand the mechanisms underlying the gender difference in the incidence of ventricular arrhythmias.