ALKBH5-mediated m6A modification of IL-11 drives macrophage-to-myofibroblast transition and pathological cardiac fibrosis in mice.

Cardiac macrophage contributes to the development of cardiac fibrosis, but factors that regulate cardiac macrophages transition and activation during this process remains elusive. Here we show, by single-cell transcriptomics, lineage tracing and parabiosis, that cardiac macrophages from circulating monocytes preferentially commit to macrophage-to-myofibroblast transition (MMT) under angiotensin II (Ang II)-induced hypertension, with accompanying increased expression of the RNA N6-methyladenosine demethylases, ALKBH5. Meanwhile, macrophage-specific knockout of ALKBH5 inhibits Ang II-induced MMT, and subsequently ameliorates cardiac fibrosis and dysfunction. Mechanistically, RNA immunoprecipitation sequencing identifies interlukin-11 (IL-11) mRNA as a target for ALKBH5-mediated m6A demethylation, leading to increased IL-11 mRNA stability and protein levels. By contrast, overexpression of IL11 in circulating macrophages reverses the phenotype in ALKBH5-deficient mice and macrophage. Lastly, targeted delivery of ALKBH5 or IL-11 receptor α (IL11RA1) siRNA to monocytes/macrophages attenuates MMT and cardiac fibrosis under hypertensive stress. Our results thus suggest that the ALKBH5/IL-11/IL11RA1/MMT axis alters cardiac macrophage and contributes to hypertensive cardiac fibrosis and dysfunction in mice, and thereby identify potential targets for cardiac fibrosis therapy in patients.

Arterial Stiffness as a Predictor of the Index of Atherosclerotic Cardiovascular Disease in Hypertensive Patients.

OBJECTIVE: The aim of this study was to evaluate the predictive value of carotid-femoral pulse wave velocity (cfPWV) and cardiovascular disease in the hypertensive population in China and to determine the specific cfPWV cut-off value for assessing future cardiovascular disease (CVD) risk. METHODS: This cross-sectional study included 630 hospital patients with primary hypertension and multiple cardiovascular risk factors or complications involving damage to clinical target organs. The study was conducted between July 2007 and October 2008. Atherosclerotic cardiovascular disease (ASCVD) risk calculations were computed according to criteria presented by the American College of Cardiology and the American Heart Association. Patients were stratified by a predefined risk threshold of 10% and divided into two groups: ASCVD ≥ 10% or ASCVD < 10%. cfPWV was used as a marker of arterial stiffness. A receiver operating characteristics (ROC) curve was applied to establish the optimal cfPWV cut-off point to differentiate between participants with and without ASCVD risk. RESULTS: In the study cohort of 630 patients (age 63.55.2 ± 8.6 years, 61.7% male) with primary hypertension, the pressure indices (augmented pressure, augmentation index [AIx], aortic pulse pressure, aortic systolic pressure [SBP]) and Framingham Risk Scores (FRS) were greater in females than in males (p < 0.001); ASCVD risk scores and peripheral diastolic pressure (DBP) were higher in males (p < 0.05). All hemodynamic indices showed a significant positive correlation with ASCVD risk scores and FRS; AIx was not correlated with ASCVD risk scores. In multivariate logistic analysis, cfPWV was significantly associated with ASCVD risk (OR: 1.324, 95% confidence interval: 1.119-1.565, p < 0.001) after adjusting for age, gender, smoking, body mass index, total cholesterol, fasting blood glucose, antihypertensive treatment, statin treatment, and DBP. In the ROC analysis, the area under the curve was 0.758 and 0.672 for cfPWV and aortic SBP (p < 0.001 and p < 0.001, respectively); the optimal critical value of cfPWV and aortic SBP was 12.45 m/s (sensitivity 63.2%, specificity 77.8%) and 124.5 mmHg (sensitivity 63.9%, specificity 65.3%). CONCLUSIONS: cfPWV is significantly correlated with the risk of ASCVD. The best cut-off value of cfPWV for assessing future CVD risk in the hypertensive population in China is 12.45 m/s.

Disparate Associations of 24-h Central Aortic and Brachial Cuff Blood Pressure With Hypertension-Mediated Organ Damage and Cardiovascular Risk.

Objective: Aim of this study was to evaluate the associations of non-invasive central aortic and peripheral (brachial) blood pressure (BP) for Hypertension-mediated organ damage (HMOD) and atherosclerotic cardiovascular disease (ASCVD) risk. Methods: We evaluated associations of HMOD with 24-h ambulatory blood pressure monitoring (ABPM) of central aortic and peripheral BP indices in patients with primary hypertension and presence of several cardiovascular risk factors. BP measurements were performed by means of a non-invasive automated oscillometric device (Mobil-O-Graph). HMOD was defined as the presence of carotid intima-media thickness (IMT) above normal values and/or carotid plaque, left ventricular hypertrophy (LVH), and/or renal abnormalities as assessed by urine albumin/creatinine ratio above normal values and/or estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. Results: In the study cohort of 273 (age 55.2 ± 13.4 years, 71.8% male) patients with primary hypertension, documented HMOD was present in 180 (65.9%), LVH in 70 (25.6%), increased IMT in 129 (47.3%). Fifty-six patients (20.5%) had kidney organ damage (20.5% albuminuria and 2.6% impaired eGFR). When accounting for confounding factors (age, sex, body-mass-index, antihypertensive treatment, smoking, triacylglycerol, statin treatment, glucose, hypoglycemic therapy, or heart rate) only peripheral 24-h pulse pressure (PP) maintained statistical significance with HMOD indices (OR: 1.126, 95% CI: 1.012~1.253; p = 0.029). Using ASCVD risk score as the independent continuous variable in multiple linear regression, 24-h central systolic pressure (SBP) (ß = 0.179; 95% CI:0.019~0.387; p = 0.031), daytime central PP (ß = 0.114; 95% CI:0.070~0.375; p = 0.005, night-time central SBP (ß = 0.411; 95% CI:0.112~0.691; p = 0.007) and night-time PP (ß = 0.257; 95% CI:0.165~0.780; p = 0.003) were all positively associated with ASCVD risk. Conclusions: Blood pressure obtained by 24-h ABPM was better correlated with HMOD than office BP. Whilst 24-h peripheral BP showed a stronger association with HMOD than 24-h central BP, the prognostic value of 24-h central BP for the 10-year ASCVD risk was superior to 24-h peripheral BP.

Shikonin Inhibits Non-Small-Cell Lung Cancer H1299 Cell Growth through Survivin Signaling Pathway.

Overexpressed survivin is associated with worse survival of several types of human tumors. In this study, the antitumor activity of shikonin in non-small-cell lung cancer (NSCLC) by regulating survivin pathway was investigated. Results showed that shikonin inhibited the NSCLC H1299 cell proliferation in a dose-dependent manner. Moreover, shikonin fits well with survivin by molecular docking. Shikonin also inhibited the mRNA expression and protein level of survivin in H1299 cells. Shikonin arrested H1299 cell cycle at the G0/G1 phase by regulating CDK/cyclin family members. In addition, shikonin regulated the expression of X-linked inhibitor of apoptosis- (XIAP-) mediated caspases 3 and 9, thus leading to the damage of mitochondrial membrane potential and induction of H1299 cell apoptosis. Overall, shikonin inhibited H1299 cell growth by inducing apoptosis and blocking the cell cycle. The underlying mechanism involves targeting survivin, which subsequently regulates the protein expression of XIAP/caspase 3/9, CDK2/4, and cyclin E/D1. Thus, shikonin, a survivin inhibitor, is a promising therapeutic strategy in NSCLC treatment.

miR-200c overexpression inhibits the invasion and tumorigenicity of epithelial ovarian cancer cells by suppressing lncRNA HOTAIR in mice.

Epithelial ovarian cancer (EOC) is a common ovarian cancer in gynecological cancers today. It has been found that microRNAs and long-chain noncoding RNA (lncRNA) regulate the gene transcriptional expression in cells. However, it is not well understood that the upstream and downstream regulatory molecules of lncRNA HOX antisense intergenic RNA (HOTAIR). The effects of miR-200c overexpression on the invasion and nude mouse tumorigenicity, as well as lncRNA HOTAIR and snail expression of EOC SKOV3 cells, should be further explored. The expression of miR-200c and lncRNA HOTAIR was detected by reverse transcription PCR (RT-PCR) in EOC SKOV3 cells. The whole miR-200c gene fragment was cloned into a lentiviral plasmid vector. The miR-200c expression in transducted SKOV3 cells with reconstructed miR-200c lentivirus was significantly higher than the negative control (P < .01). The lentivirus-miR-200c-SKOV3 cells show that the invasion ability was significantly decreased compared with the negative control (P < .01). The nude mouse tumorigenicity was significantly decreased compared with that of the control group (P < .01). The snail protein expression in lentivirus-miR-200c-SKOV3 xenograft tumor was significantly decreased compared with the negative control lentivirus-SKOV3 group (P < .05). The miR-200c overexpression significantly decreased the expressions of lncRNA HOTAIR and snail, but increased E-cadherin expression in the lentivirus-miR-200c transducted SKOV3 cells of xenograft tumor, compared with the negative control (P < .05). The miR-200c overexpression in SKOV3 cells with transducted lentivirus-miR-200c can inhibit lncRNA HOTAIR expression, decrease snail, increase E-cadherin and significantly reduce the invasion and tumorigenicity of EOC SKOV3 cells. These results suggest that the miR-200c and lncRNA HOTAIR could be effective therapeutic targets for human epithelial ovarian cancer treatment.

Central aortic pressure improves prediction of cardiovascular events compared to peripheral blood pressure in short-term follow-up of a hypertensive cohort.

Objective: The aim of this study was to assess indices of a comprehensive panel of central aortic pressure and arterial stiffness for prediction of cardiovascular events in a hypertensive cohort.Methods: Noninvasive measurements of central aortic blood pressure, brachial pressure, wave reflection augmentation index, pressure amplification, pulse wave velocity (PWV) and carotid intima-media thickness (IMT) were obtained in 675 hypertensive patients (age 61 ± 9 years, 425 males) for a mean follow-up period 25 ± 4 months. The primary endpoints were defined as cardiovascular disease (CVD) events or death from CVD.Results: After adjusting for confounding factors, central systolic (cSBP) and pulse pressure (cPP) showed higher hazard ratios (HR/10 mmHg) for cardiovascular events (CV) compared to peripheral pressure indices (pSBP, pPP) at age >60 years (cSBP: HR = 1.18, pSBP: HR = 1.17, p = 0.034; cPP: HR = 1.28, pPP: HR = 1.2, p = 0.019). Each SD increase in IMT and in central augmented pressure (cAP) entailed a 1.4 times higher risk of increased total events in elderly patients (age >60 years). For males, each SD increase in cAP was associated with 1.36 times higher risk of increased total events. For females, each SD increase in cAIx and cAP was associated with 0.4 and 0.5 times lower risk of increased total and major CV, respectively. This sex difference is most likely due to lack of age-related increase of cAIx in females after age >60 years compared to males.Conclusions: Central pressure improved prediction of CVD compared to peripheral pressure during a relatively short-term follow up of approximately 2 years at age >60 years.

Impact of new hypertension guidelines on target organ damage screening in a Shanghai community-dwelling population.

Recently, the 2017 ACC/AHA released new hypertension guidelines and proposed a redefinition of hypertension from 140/90 to 130/80 mm Hg. This study assesses the impact of the lower threshold for hypertension diagnosis on the association of hypertension with target organ damage (TOD). Health checks were conducted in a community-dwelling population in Shanghai in 2017 (N = 10 826; 43.26% mean, age 62 ± 12 years [range 29-95 years]). Subclinical TOD indices were quantified in terms of left ventricular hypertrophy (LVH) by electrocardiogram (Sokolow-Lyon standard), estimated glomerular filtration rate (eGFR), and presence of proteinuria. Information on clinical TOD was obtained by questionnaire. Arteriosclerotic cardiovascular disease (ASCVD) was determined by the 2013 ACC/ AHA recommended guidelines. Compared to the higher threshold (140/90 mm Hg), the lower threshold (130/80 mm Hg) was associated with variable rates of increased detection of hypertension and TOD: (a) Hypertension: incidence of hypertension, 29.5% (51.8%-81.5%) increase in persons with hypertension if the threshold of 130/80 mm Hg is used; (b) Subclinical TOD: LVH, 20.8%; eGFR (30-60 mL/min per 1.73 m2 ), 23.7%; proteinuria, 23.5%; (c) Clinical TOD: chronic kidney disease (CKD) IV (eGFR＜30 mL/min per 1.73 m2 ), 3.1%; diabetes (fasting glucose ≥7.0 mmol/L or HbA1C＞7.0%), 24.3%; stroke, 26.4%; chronic heart disease, 28.1%; acute myocardial infarction, 19.5% (69.4% to 88.9% of total of 36); ASCVD ≥10%, 29.3%. The lower threshold was associated with a significantly higher detection rate of clinical and subclinical TOD of approximately 20% compared to the higher threshold. 15%-20% of TOD and 29% of ASCVD were also found below the lower threshold of hypertension.

Hexokinase II promotes the Warburg effect by phosphorylating alpha subunit of pyruvate dehydrogenase.

OBJECTIVE: Tumor cells rely heavily on glycolysis regardless of oxygen tension, a phenomenon called the Warburg effect. Hexokinase II (HKII) catalyzes the first irreversible step of glycolysis and is often overexpressed in tumor cells. Mitochondrial HKII couples glycolysis and oxidative phosphorylation while maintaining mitochondrial membrane integrity. In this study, we investigated the role of HKII in promoting the Warburg effect in cancer cells. METHODS: HKII-mediated phosphorylation of the alpha subunit of pyruvate dehydrogenase (PDHA1) was tested in HEK293T cells and clear cell renal cell carcinoma (ccRCC) specimens using gene knockdown, western blotting, immunohistochemistry, and immunofluorescence. RESULTS: It was determined that HKII could not only transform glucose into glucose-6-phosphate, but also transfer the phosphate group of ATP onto PDHA1. In addition, it was found that HKII increased the phosphorylation of Ser293 on PDHA1, decreasing pyruvate dehydrogenase (PDH) complex activity and thus rerouting the metabolic pathway and promoting the Warburg effect. The overexpression of HKII correlated with the phosphorylation of PDHA1 and disease progression in ccRCC. CONCLUSIONS: The data presented here suggest that HKII is an important biomarker in the evaluation and treatment of cancer.