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Alamandine enhances cardiomyocyte contractility in hypertensive rats through a nitric oxide-dependent activation of CaMKII.

Alamandine通过一氧化氮依赖性激活CaMKII增强高血压大鼠心肌细胞收缩性。

  • 影响因子:0
  • DOI:10.1152/ajpcell.00153.2019
  • 作者列表:"Jesus ICG","Mesquita TRR","Monteiro ALL","Parreira AB","Santos AK","Coelho ELX","Silva MM","Souza LAC","Campagnole-Santos MJ","Santos RS","Guatimosim S
  • 发表时间:2020-04-01
Abstract

:Overstimulation of the renin-angiotensin system (RAS) has been implicated in the pathogenesis of various cardiovascular diseases. Alamandine is a peptide newly identified as a protective component of the RAS; however, the mechanisms involved in its beneficial effects remain elusive. By using a well-characterized rat model of hypertension, the TGR (mREN2)27, we show that mREN ventricular myocytes are prone to contractile enhancement mediated by short-term alamandine (100 nmol/L) stimulation of Mas-related G protein-coupled receptor member D (MrgD) receptors, while Sprague-Dawley control cells showed no effect. Additionally, alamandine prevents the Ca2+ dysregulation classically exhibited by freshly isolated mREN myocytes. Accordingly, alamandine treatment of mREN myocytes attenuated Ca2+ spark rate and enhanced Ca2+ reuptake to the sarcoplasmic reticulum. Along with these findings, KN-93 fully inhibited the alamandine-induced increase in Ca2+ transient magnitude and phospholamban (PLN) phosphorylation at Thr17, indicating CaMKII as a downstream effector of the MrgD signaling pathway. In mREN ventricular myocytes, alamandine treatment induced significant nitric oxide (NO) production. Importantly, NO synthase inhibition prevented the contractile actions of alamandine, including PLN-Thr17 phosphorylation at the CaMKII site, thereby indicating that NO acts upstream of CaMKII in the alamandine downstream signaling. Altogether, our results show that enhanced contractile responses mediated by alamandine in cardiomyocytes from hypertensive rats occur through a NO-dependent activation of CaMKII.

摘要

: 肾素-血管紧张素系统 (RAS) 的过度刺激与各种心血管疾病的发病机理有关。Alamandine是新鉴定为RAS的保护性组分的肽; 然而,涉及其有益作用的机制仍然难以捉摸。通过使用表征良好的高血压大鼠模型TGR (mREN2)27,我们显示mREN心室肌细胞易于通过短期alamandine (100 nmol/L) 刺激Mas相关g蛋白偶联受体成员D (MrgD) 受体介导的收缩增强,而Sprague-Dawley对照细胞显示无作用。另外,alamandine预防由新鲜分离的mREN肌细胞典型地表现出的Ca2 + 失调。因此,alamandine处理mREN肌细胞减弱了Ca2 + 火花速率并增强了对肌浆网的Ca2 + 再摄取。伴随着这些发现,KN-93完全抑制了alamandine诱导的Ca2 + 瞬时幅度和Thr17处的磷酸安邦 (PLN) 磷酸化的增加,表明CaMKII是MrgD信号通路的下游效应器。在mREN心室肌细胞中,alamandine处理诱导显著的一氧化氮 (NO) 产生。重要的是,NO合酶抑制阻止了alamandine的收缩作用,包括CaMKII位点的PLN-Thr17磷酸化,从而表明NO在alamandine下游信号传导中作用于CaMKII的上游。总之,我们的研究结果表明,高血压大鼠心肌细胞中由alamandine介导的增强的收缩反应是通过CaMKII的NO依赖性激活发生的。

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影响因子:1.44
发表时间:2020-01-01
DOI:10.1080/10641963.2019.1601205
作者列表:["Meng L","Bai X","Zheng Y","Chen D","Zheng Y"]

METHODS::Aim: We explored the role of histone modification in the association of depression-hypertension by comparing norepinephrine transporter (NET) gene levels in different depression-hypertensive patients. Then, we analyzed the expression of NET correlation with inflammatory cytokines to provide a new direction for detecting the association mechanism between depression and hypertension.Methods: NE expression levels in serum of diverse groups were detected by enzyme-linked immunosorbent assay. Then histone acetyltransferase (HAT), histone deacetylase (HDAC), H3K27ac, NET, TNF-α, and interleukin-6 (IL-6) were detected by western blot in nine female subjects in different depression and hypertension groups, and Chromatin immunoprecipitation-polymerase chain reaction (Chip-PCR) were used to confirm the degree of acetylation affecting on the transcription level of NET gene. Meanwhile, correlation between NET with TNF/IL-6 was analyzed by SPSS19.0 software program. Finally, Quantitative real-time polymerase chain reaction (qPCR) and western blot were used to detect TNF-α and IL-6 expression levels after NET overexpression or interference treatment in human umbilical vein endothelial cells and Neuro-2a cells.Results: The expression of HAT and H3K27ac had lower levels in D-H and nonD-H group than nonD-nonH group. The results showed that higher acetylation could promote expression of NET genes. Meanwhile, the expression of NET had a significant negative correlation with IL-6 (R = -0.933, p < 0.01) and tumor necrosis factor (TNF) (R = -0.817, p < 0.01) in subjects. In addition, the results confirmed that TNF-α and IL-6 mRNA and protein partial expressions could be inhibited by NET in both HUVECs and Neuronal cells (p < 0.01).Conclusion: In conclusion, differential expression of NET gene might function as an important factor in interaction between depression and hypertension by partially targeting TNF-α and IL-6.

翻译标题与摘要 下载文献
影响因子:1.62
发表时间:2020-01-01
来源期刊:Angiology
DOI:10.1177/0003319719849737
作者列表:["Dugani SB","Murad W","Damilig K","Atos J","Mohamed E","Callachan E","Farukhi Z","Shaikh A","Elfatih A","Yusef S","Hydoub YM","Moorthy MV","Mora B","Alawadhi A","Issac R","Saleh A","Al-Mulla A","Mora S","Alsheikh-Ali AA"]

METHODS::The Middle East and North Africa (MENA) region has a high burden of morbidity and mortality due to premature (≤55 years in men; ≤65 years in women) myocardial infarction (MI) and acute coronary syndrome (ACS). Despite this, the prevalence of risk factors in patients presenting with premature MI or ACS is incompletely described. We compared lifestyle, clinical risk factors, and biomarkers associated with premature MI/ACS in the MENA region with selected non-MENA high-income countries. We identified English-language, peer-reviewed publications through PubMed (up to March 2018). We used the World Bank classification system to categorize countries. Patients with premature MI/ACS in the MENA region had a higher prevalence of smoking than older patients with MI/ACS but a lower prevalence of diabetes, hypertension, and dyslipidemia. Men with premature MI/ACS had a higher prevalence of smoking than women but a lower prevalence of diabetes and hypertension. The MENA region had sparse data on lifestyle, diet, psychological stress, and physical activity. To address these knowledge gaps, we initiated the ongoing Gulf Population Risks and Epidemiology of Vascular Events and Treatment (Gulf PREVENT) case-control study to improve primary and secondary prevention of premature MI in the United Arab Emirates, a high-income country in the MENA region.

影响因子:2.49
发表时间:2020-03-01
DOI:10.1136/archdischild-2019-317131
作者列表:["Göpel W","Müller M","Rabe H","Borgmann J","Rausch TK","Faust K","Kribs A","Dötsch J","Ellinghaus D","Härtel C","Roll C","Szabo M","Nürnberg P","Franke A","König IR","Turner MA","Herting E"]

METHODS:OBJECTIVE:The aim of our study was to determine if a genetic background of high blood pressure is a survival factor in preterm infants. DESIGN:Prospective cohort study. SETTING:Patients were enrolled in 53 neonatal intensive care units. PATIENTS:Preterm infants with a birth weight below 1500 g. EXPOSURES:Genetic score blood pressure estimates were calculated based on adult data. We compared infants with high genetic blood pressure estimates (>75th percentile of the genetic score) to infants with low genetic blood pressure estimates (<25th percentile of the genetic score). MAIN OUTCOME MEASURES:Lowest blood pressure on the first day of life and mortality. RESULTS:5580 preterm infants with a mean gestational age of 28.1±2.2 weeks and a mean birth weight of 1022±299 g were genotyped and analysed. Infants with low genetic blood pressure estimates had significantly lower blood pressure if compared with infants with high genetic blood pressure estimates (27.3±6.2vs 27.9±6.4, p=0.009, t-test). Other risk factors for low blood pressure included low gestational age (-1.26 mm Hg/week) and mechanical ventilation (-2.24 mm Hg, p<0.001 for both variables, linear regression analysis). Mortality was significantly reduced in infants with high genetic blood pressure estimates (28-day mortality: 21/1395, 1.5% vs 44/1395, 3.2%, p=0.005, Fisher's exact test). This survival advantage was independent of treatment with catecholamines. CONCLUSIONS:Our study provides first evidence that a genetic background of high blood pressure may be beneficial with regard to survival of preterm infants.

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高血压方向

高血压(hypertension)是指以体循环动脉血压(收缩压和/或舒张压)增高为主要特征(收缩压≥140毫米汞柱,舒张压≥90毫米汞柱),可伴有心、脑、肾等器官的功能或器质性损害的临床综合征。高血压是最常见的慢性病,也是心脑血管病最主要的危险因素。临床上高血压可分为两类:原发性高血压和继发性高血压。

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