应激状态下的心脏自噬:自噬作用是有益还是有害?

自噬(autophagy)广泛参与各种生理和病理过程,是目前生物医学领域研究的热点之一。自噬的过程涉及到一系列复杂的调控基因产物以及组合机制、靶向性选择、自噬体形成以及内含物降解等的协同作用。在心脏疾病中,如缺血再灌注、心肌肥厚和心力衰竭的发生和发展中都能检测到自噬的存在。本综述主要探讨自噬调节在心脏疾病发生和发展中的作用和意义。     

心肌自噬的生理与病理生理作用

自噬是生物体内普遍存在的一种降解长寿命蛋白质和细胞器的分解代谢过程。一定程度的自噬是一种内源性细胞保护机制,并参与适应性免疫反应;自噬不足或过度造成细胞稳态失调,加剧或导致细胞死亡。疾病和应激刺激可以造成心肌自噬活性明显增高,参与多种心脏疾病的发生和发展。调控心肌自噬可能成为心血管疾病和心力衰竭治疗的潜在靶点之一。本文综述心肌自噬的生理与病理生理意义及其分子机制,为心肌损伤和相关疾病防治提供新思路。     

MicroRNAs在心血管自噬中的调节作用

自噬作为一种进化上高度保守的细胞降解途径,其调节异常与心血管疾病的发生、发展密切相关.研究显示,在心血管系统中,基础水平自噬对维持心肌正常收缩和传导至关重要,而在缺血/再灌注损伤和心力衰竭等心血管病理状态下,自噬水平明显增强.细胞自噬是一种多基因参与的复杂过程,近年来越来越多的证据表明,microRNAs(miRNAs)在心血管系统发育、正常生理功能维持以及不同心血管疾病(cardiovascular disease,CVDs)自噬中具有重要调节作用.本文通过对miRNAs与CVDs自噬调节方面的进展进行归纳,针对miRNAs对CVDs自噬的潜在机制进行总结,望为心血管疾病的诊断和治疗提供新的方向.     

运动训练调控细胞自噬相关机体功能的分子机制研究进展

细胞自噬是真核细胞中广泛存在的一种自我保护机制,是细胞在应激情况下通过溶酶体或液泡高度保守的降解途径将细胞内异常蛋白和细胞器降解为生物大分子,重新被细胞利用的过程。适度的运动锻炼可以诱导机体多种组织细胞自噬的激活,增强机体的活力,延缓机体的衰老。运动训练可以刺激骨骼肌细胞自噬水平上调,延缓骨骼肌衰老;运动训练作为一种机械性刺激可以通过调节心肌细胞的自噬激活调控长寿命或错误折叠心肌蛋白和受损细胞器的代谢,延缓心肌衰老;此外,细胞自噬与糖尿病、肿瘤、脑血管疾病、衰老及心脏病等密切相关,运动训练可以预防动脉粥样硬化等血管类疾病的发生,也可以通过调控细胞自噬来预防与治疗心脏病、中风、糖尿病等疾病。现主要论述细胞自噬的涵义与分类,细胞自噬不同阶段的分子机制,以及运动训练通过调控细胞自噬相关基因调控骨骼肌、心肌和自噬相关疾病的分子机制,为使用科学的运动训练方式来提高机体功能及预防和治疗疾病提供了理论依据。     

胰岛素样生长因子I对心脏的作用

胰岛素样生长因子I(IGF I)是属于胰岛素家族的一种多肽。它可促进心脏生长发育 ,增强心脏功能 ,参与心肌肥厚、心力衰竭和心肌细胞凋亡等病理过程。本文对心脏的IGF I来源及其受体、IGF I的心脏效应及可能的机制进行综述。IGF I对心脏疾病 (心肌肥厚、心力衰竭等 )的防治有潜在的临床应用价值。     

自噬:心血管疾病治疗的新靶点

心血管疾病严重危害人类健康,是全球首要死亡原因。研究发现自噬与心血管疾病的发生、发展密切相关,并且在心肌细胞、心脏成纤维细胞、内皮细胞、血管平滑肌细胞以及巨噬细胞中得到广泛研究。细胞自噬在维持心血管系统稳态及功能方面至关重要,过度或不足的自噬流则可导致心血管系统疾病。本文不仅论述自噬在心血管细胞和疾病中的调控机制及作用,还探讨了自噬作为心血管疾病潜在的治疗靶点,为今后心血管疾病的研究和防护开拓了新的思路。     

钙网蛋白在心肌肥大中的研究进展

钙网蛋白(calreticulin, CRT)是内质网中主要的Ca2+结合分子伴侣,具有调控细胞Ca2+稳态、蛋白质合成与修饰等作用,参与调节细胞凋亡、应激、心血管炎症反应等多种生理和病理生理过程.CRT属于心脏胚胎基因家族,通过调节心肌细胞肌原纤维形成、促进糖原分解、诱导肥大相关基因转录、调节心脏传导系统发育及心肌细胞凋亡等,在心脏发育及心肌肥大的发生、发展过程起重要作用,本文对CRT在心肌肥大中的作用及其信号转导途径予以综述.     

力学刺激诱导细胞自噬的研究进展

自噬是细胞重要的自我保护机制,多种伤害性刺激激活的自噬具有维持细胞稳态和正常功能的作用.此外,自噬还参与调控恶性肿瘤、动脉粥样硬化等多种疾病的发生发展过程.体内细胞处于复杂的力学微环境中,力学刺激参与调控细胞自噬,如压力可诱导心肌细胞的自噬、牵张力调控运动系统多种细胞的自噬、流体剪切力可激活血管内皮细胞和肿瘤细胞的自噬.力学刺激诱导的细胞自噬依赖众多信号通路.细胞骨架作为重要的调节因子,不仅参与细胞力学信号转导,同时可参与调控细胞自噬.因此,细胞骨架与力学刺激诱导的细胞自噬密切相关.本文结合最新的研究成果,综述力学刺激对细胞自噬的影响及其分子机制,以期为研究力学刺激对细胞生物学行为的影响提供新的视角,进而为相关疾病的治疗提供新思路和分子靶点.     

巨自噬在心脏疾病调节中的双向作用

巨自噬是一种普遍存在的,由溶酶体介导,降解长寿命蛋白质和细胞器的分解代谢过程.巨自噬对心脏疾病调节有双向作用:通过清除损伤的细胞器和蛋白质聚合物,维持内环境稳定,促进细胞存活;严重损伤时,巨自噬过度激活导致心肌细胞死亡.本文综述巨自噬在心脏疾病调节中的研究进展,包括巨自噬的形成和凋亡的关系,探讨巨自噬作为调节因子,对缺血-再灌注、心肌肥大和心力衰竭的双向作用,为疾病治疗开辟新思路.     

Sfrp1通过阻断Wnt信号通路减轻血管紧张素Ⅱ诱导的心脏损伤并促进自噬的研究

摘要 目的：本研究旨在评估Sfrp1在血管紧张素II诱导的心肌肥厚中的心脏保护作用，并探讨其与自噬和Wnt信号通路相关的可能机制。方法：利用重组AAV9载体将Sfrp1导入Ang II诱导的肥厚型H9C2心肌细胞。用CCK8测定细胞活力。流式细胞仪检测细胞凋亡率。用显微照片记录肥厚细胞大小的变化。western blot检测Sfrp1、Bcl-2、Bax、CytC、Caspase-3、P62、ATG5、Beclin、LC3、β-catenin和DVL1的蛋白表达。通过qRT-PCR检测β-连环蛋白和DVL1的mRNA表达。自噬抑制剂3-MA也用于验证治疗过程中自噬的参与。结果：（1）Sfrp1成功转染H9C2细胞，其过度表达减轻了心肌肥厚。（2）经过AAV9-Sfrp1预处理可减少肥厚心肌的细胞凋亡，可逆转Ang II组自噬相关蛋白（p62、ATG5、Beclin、LC3）的表达；（3）自噬在治疗心肌肥厚过程中的作用通过可自噬抑制剂3-MA来证实。（4）激活的Wnt信号（β-连环蛋白，DVL1）也被AAV9-Sfrp1抑制。结论：Sfrp1通过Wnt信号通路促进细胞自噬，从而保护心肌细胞免受肥厚性损伤和凋亡，这为Sfrp1对心肌肥厚的心肌保护作用机制提供了一个重要的视角。     

自噬在急性心肌梗死发病中作用的研究进展

自噬是生物细胞内普遍存在且高度保守的一种生理过程,其通过溶酶体融合降解细胞内的大分子组分、受损的细胞器以及侵入胞内的病原菌,以达到维持细胞稳态的目的。自噬在多种疾病的发生发展中也发挥十分重要的作用,尤其是心血管疾病。自噬对其病程的发展可以发挥两种截然不同的作用。适当的自噬作用可以降低炎症反应和氧化应激促进细胞的存活,以及通过减少泡沫细胞的形成而对维持心血管的正常功能起一个保护作用;但过度的自噬作用会对细胞造成不可逆的损伤,诱导细胞发生不依赖于caspase的自噬性细胞死亡,增加局部的炎症反应,从而促进动脉粥样硬化病变的发展。本文就自噬在急性心肌梗死发生发展中作用的研究进展进行了综述,探讨自噬成为预防及治疗心血管疾病新靶标的可能性。     

Autophagy in cardiovascular disease

Autophagy is a major cytoprotective pathway that eukaryotic cells use to degrade and recycle cytoplasmic contents. Recent evidence indicates that autophagy under baseline conditions represents an important homeostatic mechanism for the maintenance of normal cardiovascular function and morphology. By contrast, excessive induction of the autophagic process by environmental or intracellular stress has an important role in several types of cardiomyopathy by functioning as a death pathway. As a consequence, enhanced autophagy represents one of the mechanisms underlying the cardiomyocyte dropout responsible for the worsening of heart failure. Successful therapeutic approaches that regulate autophagy have been reported recently, suggesting that the autophagic machinery can be manipulated to treat heart failure or to prevent rupture of atherosclerotic plaques and sudden death.     

自噬在疾病中的双重作用

自噬是细胞的一种正常的生理活动,参与细胞内损伤的蛋白质和亚细胞器经溶酶体途径降解的过程。自噬可以抵御外界的不良环境,在多种疾病中起着重要作用。近年来,大量研究表明自噬在细胞新陈代谢和生理功能上有双重作用,在疾病发生的不同时期,自噬起到不同的作用。通常情况自噬可以及时的清除细胞内损伤的蛋白质,作为一种细胞的保护机制,但是自噬的持续活化,导致细胞内大量蛋白质的降解,使细胞无法维持其基本结构,最终将导致细胞坏死或凋亡。自噬、凋亡和坏死的转化,很有可能受到p53、Bcl-2、Beclin-1、ATG5、TG2及p62等信号分子调控。肝脏和心脏是维持人体生命活动的重要器官,自噬在脂肪肝、肝硬化、心肌梗塞及心脏衰竭等疾病中扮演着重要的角色。本文总结了自噬、凋亡及坏死的相互关系,自噬在疾病中的双重作用,并重点介绍自噬在肝脏和心脏疾病中的作用。     

Deconvoluting the relationships between autophagy and metastasis for potential cancer therapy

Autophagy is a highly conserved lysosome-dependent degradation process that may digest some long-lived proteins and damaged organelles. As an essential homeostasis maintaining system in normal cells, autophagy plays a key role in several pathological settings, especially cancer. Metastasis, known as a crucial hallmark of cancer progression, is the primary cause of cancer lethality. The role of autophagy in metastasis is quite complex as supportive evidence has indicated both pro-metastatic and anti-metastatic functions of autophagy. Autophagy can inhibit metastasis by restricting necrosis and mediating autophagic cell death, whereas it may also promote metastasis by enhancing cancer cell fitness in response to stress. Moreover, the function of autophagy is context- and stage-dependent. Specifically, during the early steps of metastasis, autophagy mainly serves as a suppressor, while it plays a pro-metastatic role in the later steps. Here, we focus on highlighting the dual roles of autophagy in metastasis and address the molecular mechanisms involved in this process, which may provide a new insight into cancer biology. While, we also summarize several anti-metastatic agents manipulating autophagy, in the hope of shedding light on exploration of potential novel drugs for future cancer therapy.     

Mechanisms of mitochondria and autophagy crosstalk

Autophagy is a cellular survival pathway that recycles intracellular components to compensate for nutrient depletion and ensures the appropriate degradation of organelles. Mitochondrial number and health are regulated by mitophagy, a process by which excessive or damaged mitochondria are subjected to autophagic degradation. Autophagy is thus a key determinant for mitochondrial health and proper cell function. Mitophagic malfunction has been recently proposed to contribute to progressive neuronal loss in Parkinson's disease. In addition to autophagy's significance in mitochondrial integrity, several lines of evidence suggest that mitochondria can also substantially influence the autophagic process. The mitochondria's ability to influence and be influenced by autophagy places both elements (mitochondria and autophagy) in a unique position where defects in one or the other system could increase the risk to various metabolic and autophagic related diseases.     

Functions of Autophagy in Pathological Cardiac Hypertrophy

Pathological cardiac hypertrophy is the response of heart to various biomechanical and physiopathological stimuli, such as aging, myocardial ischemia and hypertension. However, a long-term exposure to the stress makes heart progress to heart failure. Autophagy is a dynamic self-degradative process necessary for the maintenance of cellular homeostasis. Accumulating evidence has revealed a tight link between cardiomyocyte autophagy and cardiac hypertrophy. Sophisticatedly regulated autophagy protects heart from various physiological and pathological stimuli by degradating and recycling of protein aggregates, lipid drops, or organelles. Here we review the recent progresses concerning the functions of autophagy in cardiac hypertrophy induced by various hypertrophic stimuli. Moreover, the therapeutic strategies targeting autophagy for cardiac hypertrophy will also be discussed.     

Autophagy and cancer

Autophagy is a homeostatic and evolutionarily conserved mechanism of self-digestion by which the cells degrade and recycle long-lived proteins and excess or damaged organelles.Autophagy is activated in response to both physiological and pathological stimuli including growth factor depletion,energy deficiency or the upregulation of Bcl-2 protein expression.A novel role of autophagy in various cancers has been proposed.Interestingly,evidence that supports both a positive and negative role of autophagy in the pathogenesis of cancer has been reported.As a tumor suppression mechanism,autophagy maintains genome stability,induces senescence and possibly autophagic cell death.On the other hand,autophagy participates in tumor growth and maintenance by supplying metabolic substrate,limiting oxidative stress,and maintaining cancer stem cell population.It has been proposed that the differential roles of autophagy in cancer are disease type and stage specific.In addition,substrate selectivity might be involved in carrying out the specific effect of autophagy in cancer,and represents one of the potential directions for future studies.     

Autophagy: for better or for worse

Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism protecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numerous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immunity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.