转录因子GATA-4在心肌分化、肥厚及凋亡中的作用

锌指结构家族成员GATA-4作为一种特定的细胞核转录因子,涉及基因调节的不同环节,控制着基因的表达和功能的调节,正日益受到高度重视.该文系统阐述了GATA-4因子的结构、表达及其在心脏发育、心肌肥厚和抗心肌细胞凋亡方面的作用.     

脊椎动物心肌基因表达的分子调控

鉴定在心脏发育过程中指导心脏形成的分子途径,将对心脏是如何形成和这些途径的打断如何导致先天性以及后天性心脏病的发生提供一个基本的认识,尽管脊椎动物骨骼肌和心肌看起来很相似,然而,它们的细胞谱系的特化和模式化是由不同的基因推动的,已知有几个转录因子家族在心肌发育和模式建成中发挥重要作用,包括MADS同源盒蛋白MEF2和SRF,螺旋-环-螺旋HAND因子,锌指GATA-4/5/6因子和NK-2同源异型因子,这些转录因子能激活心脏目标基因,从而调控心肌基因的表达.     

锌指蛋白与心脏发育

锌指是最大的DNA结合蛋白家族,是最普遍的核酸识别元件.近年来发现锌指参与生物体的基因转录,复制及蛋白质的合成等各种基因调节和控制过程,心脏发育过程中涉及大量锌指基因.综述了心脏发育过程中起重要调控作用的锌指蛋白以及它们的作用机制.     

Islet1基因与心脏发育

心脏发育及心脏疾病干细胞的治疗要求对心脏发育过程中的控制细胞增殖及分化的相关基因的作用机制进行深入了解.Islet1基因(Isl1基因)含有6个外显子和5个内含子,定位于人类5号染色体5q11.2.该基因在基因组内约占12kb,目前所知其最长可读框(ORF)至少由5个外显子组成,编码一个由384个氨基酸组成的转录因子蛋白.最近研究发现,不同的心脏细胞可能源于同一种多能心脏祖细胞—Isl1+细胞,心脏的这一发育模式与血液细胞的形成模式非常相像.另外有研究结果显示,Isl1是与心脏发育密切相关的转录因子之一,其表达随着心脏发育成熟而逐渐下调.虽然针对Isl1基因做了较多的研究工作,但是它表达调控的具体模式及发挥功能的详细作用机制目前仍未完全清楚,本文对最近几年Isl1基因的研究进展作一综述.     

果蝇心脏发育研究三十年进展

果蝇(Drosophila melanogaster)作为最早用于研究心脏发育基因调控的模式生物,已经走过三十年的历程。果蝇心脏发育过程经历了胚胎期、幼虫期和成虫期三大阶段。在胚胎早期, Tinman、Dorsocross和Pannier等基因是关键的调控因子。Tinman参与最早的心脏前体细胞分化和心脏细胞形成,而Dorsocross和Pannier则影响心脏前体细胞的定向分化和心脏管腔的形成。进入胚胎晚期和幼虫期,果蝇的心管经历进一步的发展和重塑,该过程主要受到转录因子Hand、Mef2以及Hox基因家族的调控。在成虫期, Hox基因家族和Tinman依旧发挥重要作用。虽然果蝇心脏与脊椎动物成熟心脏存在形态上的差异,但两者心脏的早期发育过程以及调控基因和信号通路都有保守性。本文综述了果蝇心脏发育基因调控研究的三十年进展以及利用果蝇模型研究人类心脏相关疾病的潜在希望。     

HEY转录因子的研究进展

Hey属于bHLH(碱性螺旋-环-螺旋)转录因子,具有bHLH和Orange两个结构域.Hey蛋白是Notch信号通路的直接靶基因,在发育决定中起着很重要的作用,例如神经系统、骨骼、骨骼肌、血管、心脏等的发育.研究Hey的发育调控的机制,可以帮助我们更好地理解它们的生物学功能及其在临床诊断和治疗中的重要作用.     

TFIID在配子发生和早期胚胎发育过程中的作用

配子发生以及胚胎早期发育过程受严格且有序的基因表达调控。多种转录因子与靶基因结合,激活基因的时空特异性表达,实现受精卵全能性的获得,完成母型基因组转录调控向合子基因组转录调控的转变以及随后胚胎细胞的分化调节。研究表明,TFIID转录因子家族在这些关键阶段起重要作用,在基因转录调节的起始阶段,TFIID转录因子家族成员作为通用转录因子被招募到靶基因的启动子上,与其他转录因子共同形成转录前起始复合物,起始转录。该文总结了TFIID转录因子的结构、作用方式,以及在配子发生和早期胚胎发育中的调控作用。     

同源（异位）框转寻因子及其对心血管系统的调节作用

同源（异位）框转录因子是由同源框基因所编码的一种区域特异性的转录调控因子,它影响多种细胞的分化增殖和迁移过程,心血管系统组织内有某些同源框基因的表达,提示这些调控因子可能参与了心脏的正常生长发育和某些病理性细胞分化增殖的过程。     

植物WRKY转录因子结构及功能研究进展

WRKY蛋白是植物所特有的转录因子家族.因WRKY结构域中的N-端均含有高度保守的WRJKYGQK氨基酸序列而得名.它能够与(T)TGACC(A/T)序列(W*box)发生特异性作用,调节启动子中含W-box元件的调节基因或功能基因的表达,从而参与植物的各种防卫反应,调节植物的发育和代谢等.近些年来.有关WRKY转录因子的研究很多,如模式生物中的拟南芥和水稻基因组中拥有大量的WRKY成员.主要介绍WRKY转录因子的结构特点及生物学功能.     

MicroRNA与动物发育

MicroRNA(miRNA)是一类约22nt大小的内源性非编码RNA,它们通过剪切靶基因的转录产物或者抑制转录产物的翻译从而起到转录后调控靶基因表达的作用。在动物体内,通过基因敲除等方法所进行的大量研究表明了miRNA参与了胚胎早期发育、脑及神经发育、心脏发育、肌肉及骨骼发育等动物发育的各个方面。miRNA是动物发生发育过程中重要的调控因子。主要介绍了近年来miRNA在动物生长发育过程中的研究进展。     

Myocardial protective effect of octylguanidine against the damage induced by ischemia reperfusion in rat heart

This study shows that the hydrophobic cation octylguanidine protects against myocardial damage induced by ischemia-reperfusion. The protective effect of the amine was analyzed after 5 min of coronary occlusion followed by 5 min reperfusion in rat hearts. ECG tracings from rats treated with an i.v. injection of 5 mg/kg of octylguanidine showed a total absence of post-reperfusion arrhythmias, conversely to what was observed in untreated rats. The histological images showed that myocardium fibers from treated rats were in good shape and retained their striae, also there was absence of edema. Furthermore, the accumulation of ²⁰¹Tl in hearts from these rats indicated that the tissue did not suffer disruption or impairment in membrane functions. The above correlated with the fact that mitochondria isolated from the ventricular free wall from treated rats preserved their ability to synthesize ATP. We propose that the protective effect of octylguanidine might be due to its documented inhibitory action on the opening of mitochondrial non-specific pores, a mechanism which is associated in heart injury as induced by reperfusion. (Mol Cell Biochem 269: 19–26, 2005)     

Guidelines for heart transplantation

Based on the changes in the field of heart transplantation and the treatment and prognosis of patients with heart failure, these updated guidelines were composed by a committee under the supervision of both the Netherlands Society of Cardiology and the Netherlands Association for Cardiothoracic surgery (NVVC and NVT). The indication for heart transplantation is defined as: ‘End-stage heart disease not remediable by more conservative measures’. Contraindications are: irreversible pulmonary hypertension/elevated pulmonary vascular resistance; active systemic infection; active malignancy or history of malignancy with probability of recurrence; inability to comply with complex medical regimen; severe peripheral or cerebrovascular disease and irreversible dysfunction of another organ, including diseases that may limit prognosis after heart transplantation. Considering the difficulties in defining end-stage heart failure, estimating prognosis in the individual patient and the continuing evolution of available therapies, the present criteria are broadly defined. The final acceptance is done by the transplant team which has extensive knowledge of the treatment of patients with advanced heart failure on the one hand and thorough experience with heart transplantation and mechanical circulatory support on the other hand. (Neth Heart J 2008;16:79-87.)     

心外膜的发育

心外膜是覆盖在心脏外层的间皮组织。心外膜来源于脏壁中胚层的前心外膜,后者位于心管流入极附近。心外膜的部分细胞通过上皮间充质转化进入心外膜下层,随后形成血管内皮、成纤维和平滑肌细胞,最终导致冠脉系统的形成。心外膜细胞可能形成心肌细胞,并且可能是心脏驻留干细胞的来源。因此,它在心脏修复治疗中发挥巨大作用。本文回顾了该领域的最新研究进展并且提出了目前存在的问题。     

Left ventricular assist device: a functional comparison with heart transplantation

Background A growing number of patients with end-stage heart failure undergo implantation of ventricular assist devices as a bridge to heart transplantation. Objectives In this study we investigated whether functional and haemodynamic recovery after implantation is sufficient to warrant the use of them as long-term alternative to heart transplantation. Methods We compared peak VO₂ of a group of patients three months after implantation of a ventricular assist device and three months after heart transplantation. Furthermore, we analysed the degree of haemodynamic recovery, by comparing plasma levels of BNP and creatinine before and after implantation of the device. Results After implantation of a ventricular assist device, exercise capacity improved considerably; three months after implantation peak VO₂ was 20.0±4.9 ml/kg/min (52% of predicted for age and gender). After heart transplantation exercise capacity improved even further; 24.0±3.9 ml/ kg/min (62% of predicted for age and gender) (p<0.001). In the three months after implantation, BNP plasma levels decreased from 570±307 pmol/l to 31±25 pmol/l and creatinine levels decreased from 191±82 μmol/l to 82±25 μmol/l, indicating significant unloading of the ventricles and haemodynamic recovery. Conclusion With regard to functional and haemodynamic recovery, the effect of implantation of a ventricular assist device is sufficient to justify its use as an alternative to heart transplantation. (Neth Heart J 2008;16:41-6.)     

The fibroblast growth factor signaling axis controls cardiac stem cell differentiation through regulating autophagy

The fibroblast growth factor (FGF) signaling axis plays important roles in heart development. Yet, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood. Using genetically engineered mouse and in vitro cultured embryoid body (EB) models, we demonstrate that FGF signaling suppresses premature differentiation of heart progenitor cells, as well as autophagy in outflow tract (OFT) myocardiac cells. The FGF also promotes mesoderm differentiation in embryonic stem cells (ESCs) but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, inhibition of FGF signaling increases myocardial differentiation and autophagy in both ex vivo cultured embryos and EBs, whereas activation of autophagy promotes myocardial differentiation. Thus, a link between FGF signals preventing premature differentiation of heart progenitor cells and suppression of autophagy has been established. These findings provide the first evidence that autophagy plays a role in heart progenitor differentiation, and suggest a new venue to regulate stem/progenitor cell differentiation.     

The fibroblast growth factor signaling axis controls cardiac stem cell differentiation through regulating autophagy

The fibroblast growth factor (FGF) signaling axis plays important roles in heart development. Yet, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood. Using genetically engineered mouse and in vitro cultured embryoid body (EB) models, we demonstrate that FGF signaling suppresses premature differentiation of heart progenitor cells, as well as autophagy in outflow tract (OFT) myocardiac cells. The FGF also promotes mesoderm differentiation in embryonic stem cells (ESCs) but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, inhibition of FGF signaling increases myocardial differentiation and autophagy in both ex vivo cultured embryos and EBs, whereas activation of autophagy promotes myocardial differentiation. Thus, a link between FGF signals preventing premature differentiation of heart progenitor cells and suppression of autophagy has been established. These findings provide the first evidence that autophagy plays a role in heart progenitor differentiation, and suggest a new venue to regulate stem/progenitor cell differentiation.     

新型机械心脏瓣膜的研究

目前临床使用的各种机械心脏瓣膜的主要问题是血栓栓塞和与抗凝治疗有关的出血,其缺陷在于瓣膜开启时,碟片和支架将瓣膜的整个血流通道分隔成三至四个较小的血流通道。在这种受阻隔的血流通宫,形成容易诱发血栓的高剪应力区、紊流和滞流区。我们研制的两种机械心脏瓣膜在瓣膜开启时,没有任何支架和碟片分隔瓣膜的血流通道,使血流与天然心脏瓣膜中的相类似,可减少对血液的危害,从而可减少换瓣病人对抗凝治疗的依赖程度。     

Improved methods for automatic monitoring of contracting heart cells in culture

The present communication describes improved methods for isolating and plating beating heart cells from neonatal rats using collagenase and collagen-coated petri dishes. The amplitude and frequency of contraction are continuously and simultaneously measured under well defined conditions and during prolonged periods of time with a highly sensitive and thermostated instrument. Additions, e.g. drugs and toxic agents, are made through an accessory pump system that involves extensive dilution of the added compound with medium; aliquots of medium can be withdrawn for estimation of metabolites. The system described is reliable and relatively inexpensive and allows a more extensive use of isolated heart cells, especially in studies of heart functions where small changes in amplitude and frequency of beating during prolonged periods of time are important.     

一种袖珍式胎心音仪的设计和实现

研制出一种简单实用、安全可靠并具有广阔市场前景的袖珍式胎心音仪。该仪器利用超声多普勒原理,用超声探头从母体腹部提取胎儿心音信号,经过信号解调及低频放大、音频功率放大等处理,然后由耳机及扬声器输出胎心音。     

用心率变异功率谱研究出生后心率变慢的机理

目的 :探讨神经机制及心源性因素在出生后心率变慢中的作用。方法 :运用心率变异性的频域和时域分析方法 ,主要为功率谱分析方法 ,以不同年龄组的人和家兔为实验对象 ,对出生后心脏的自主神经调控进行初步探讨 ;并通过观察不同年龄组离体灌流兔心 (无神经体液因素影响 )自律性的变化 ,探讨心脏本身因素是否参与出生后心率变慢的调控。结果 :人和家兔迷走交感对心率的调控作用比在各年龄组之间有显著差异 ,且随年龄增长逐渐升高 ;家兔离体心脏的自主心率在各年龄组之间有显著差异 ,且随年龄增长逐渐降低。结论 :出生后心率减慢与神经机制有关 ,也有心脏本身因素的参与