巨噬细胞自噬在动脉粥样硬化中的作用

自噬通过溶酶体依赖的降解途径维持细胞稳态。最新研究显示巨噬细胞自噬可以促进胆固醇流出,抑制炎症体活化从而抑制动脉粥样硬化进展。在进展期斑块内,巨噬细胞自噬水平降低,斑块易损性增高,极易导致斑块破裂,引起急性冠脉综合征。因此,调控巨噬细胞自噬已成为心血管领域的关注热点,深入探究其机理将为动脉粥样硬化的防治提供新思路。     

慢性内质网应激诱导的凋亡在动脉粥样硬化斑块形成中的作用

内质网应激(ERS)与促进动脉粥样硬化(As)的非动脉壁系统和动脉壁系统因素均密切相关。未折叠蛋白反应(UPR)作为ERS长期激活的标志,可导致细胞的病理状态及组织功能受损。已有大量研究表明As斑块内的细胞,尤其是易损斑块区域的内皮细胞和巨噬细胞均表现有UPR被慢性激活。病理性的慢性ERS通过诱导细胞(内皮细胞、巨噬细胞及平滑肌细胞)凋亡而促进坏死核形成,激活炎症信号通路,影响易损斑块的形成与稳定性,有重要的促As效应。造成慢性ERS的应激源:氧化应激、氧化型胆固醇、细胞内高水平胆固醇及饱和脂肪酸等在As病程中表现明显,且在肥胖、胰岛素抵抗及糖尿病等促进As临床病程的因素中更为突出。近年研究已经部分揭示了ERS促As易损斑块形成的机制及体内的相关性,为ERS药物靶向性治疗途径提供了思路,但仍需大量深入的研究才能转化为具有临床意义的防治方法。     

巨噬细胞自噬与动脉粥样硬化的关系及相关中药研究进展

自体吞噬(自噬)是由溶酶体介导的降解细胞质内受损的细胞器或蛋白质的代谢过程。适度的自噬对动脉粥样硬化具有保护作用,过度自噬会导致细胞死亡,不利于斑块的稳定性。巨噬细胞在动脉粥样硬化斑块进展中起重要作用,自噬是影响巨噬细胞在动脉粥样硬化中生存的分子细胞机制,直接影响动脉粥样硬化进程。本研究对自噬在动脉粥样硬化中的双重作用、巨噬细胞自噬对干预动脉粥样硬化的意义、中药对巨噬细胞自噬的影响及其在动脉粥样硬化防治中的潜在意义进行综述。     

巨噬细胞铁代谢Hepcidin-Fpn1轴及其在动脉粥样硬化的作用

动脉粥样硬化(As)与铁代谢相关联,但斑块中聚集的铁是产生致病作用还是只是在As疾病发生发展过程中溶血等导致的一个单纯后果还存在争议。巨噬细胞在As斑块的形成和发展中发挥关键作用。本文总结巨噬细胞铁代谢与As的研究进展。首先介绍在巨噬细胞铁代谢中发挥重要作用的Hepcidin-Fpn1轴;接着从炎症、感染、斑块内出血3个方面介绍巨噬细胞铁代谢对As发生发展的影响;最后介绍与铁代谢相关的As治疗的新思路。     

巨噬细胞自噬在动脉粥样硬化病理机制中的研究进展

巨噬细胞在动脉粥样硬化免疫应答中发挥着重要作用,巨噬细胞自噬作为动脉粥样硬化新的参与者也获得普遍共识。巨噬细胞自噬是由溶酶体系统降解胞内受损、变性及衰老的蛋白质与细胞器的过程,基础水平的自噬可保护细胞免受环境刺激影响,对于控制动脉粥样硬化进程具有重要意义,反之过度自噬则导致细胞死亡,斑块失稳。本文拟从炎症、内质网应激以及活性氧类等角度对自噬在动脉粥样硬化中的作用及机制作一综述。     

脂噬在动脉粥样硬化中的作用及中医药干预研究进展

动脉粥样硬化(As)是一种多因素共同作用的慢性炎症性血管病变。脂质蓄积是As发生的关键病理因素之一,其通过触发血管内炎症细胞浸润、内皮细胞损伤、泡沫细胞形成、血管平滑肌细胞增殖及迁移等多个病理环节,最终导致As斑块形成。脂噬作为一种选择性的自噬进程,通过溶酶体介导选择性降解细胞内储存中性脂质的细胞器脂滴,减少脂质沉积,从而维持细胞稳态,成为As研究的新靶点。本文对细胞脂噬功能在As中的作用的研究进展及相关中医药治疗进行讨论,旨在从脂噬角度为中医药防治As提供可行性思路。     

不要低估血管平滑肌细胞在动脉粥样硬化斑块形成中的作用

血管内皮细胞、平滑肌细胞(SMC)和巨噬细胞共同参与动脉粥样硬化(As)斑块形成。近年研究表明,SMC来源的细胞占As斑块中细胞总数的70%以上。As斑块中的SMC通过自分泌细胞因子促进自身的增殖、迁移和炎症反应,通过旁分泌激活单核/巨噬细胞并将其募集到As损伤部位,同时通过其细胞膜表面表达的脂蛋白受体摄取脂质形成泡沫细胞。SMC在As斑块形成中扮演十分重要的角色,应进一步深化对SMC在As发生发展中的作用及作用机制的研究。     

ABCA1在冠心病及其发病机制中的研究新进展

动脉粥样硬化(As)是冠心病的主要病因,而泡沫细胞又是As的主要病因,过多的胆固醇在巨噬细胞中积累形成泡沫细胞,因此减少胆固醇的积累从而减少泡沫细胞的形成可能成为治疗As有效的方法。ATP结合盒转运体A1(ABCA1)可使细胞内胆固醇和磷脂转运到载脂蛋白AⅠ(Apo AⅠ)形成高密度脂蛋白前体,使过多的胆固醇进入肝脏重新利用或经胆汁和粪便排出,这个过程就是胆固醇逆转运。ABCA1还能够抑制As的炎症反应,引起血管内皮细胞变化,参与氧化应激反应,可通过多种代谢通路影响As,其不同的基因型对As的影响也不相同。因此,ABCA1在As的发生发展中具有举足轻重的作用。     

选择性自噬和动脉粥样硬化

选择性自噬对降解的底物蛋白具有专一性,包括线粒体自噬、脂噬、炎症小体自噬、内质网自噬、过氧化物酶体自噬、聚集体自噬、核糖体自噬等。动脉粥样硬化(As)是一种慢性炎症性病变,其主要特征包括脂质堆积、泡沫细胞形成、内皮细胞功能障碍、血管平滑肌细胞异常增殖和局部炎症。近年来,大量研究提示选择性自噬参与As的发生发展。文章综述了选择性自噬的调控机制,以及线粒体自噬、脂噬、炎症小体自噬、内质网自噬和过氧化物酶体自噬在As中的作用及其分子机制,以期为As的防治提供新思路。     

巨噬细胞自噬:稳定动脉粥样硬化斑块的潜在治疗靶点

巨噬细胞能够摄取脂蛋白,积累脂质,形成泡沫细胞,并释放多种酶、炎症介质,在动脉粥样硬化的发生、进展中起重要作用。研究发现,诱导巨噬细胞自噬能够稳定动脉粥样硬化斑块。该文主要介绍巨噬细胞自噬在动脉粥样硬化中的作用,以及其作为治疗靶点稳定动脉粥样硬化斑块的研究成果。     

Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis

Endoplasmic reticulum (ER) is a dynamic organelle that participates in a number of cellular functions by controlling lipid metabolism, calcium stores, and proteostasis. Under stressful situations, the ER environment is compromised, and protein maturation is impaired; this causes misfolded proteins to accumulate and a characteristic stress response named unfolded protein response (UPR). UPR protects cells from stress and contributes to cellular homeostasis re‐establishment; however, during prolonged ER stress, UPR activation promotes cell death. ER stressors can modulate autophagy which in turn, depending of the situation, induces cell survival or death. Interactions of different autophagy‐ and apoptosis‐related proteins and also common signaling pathways have been found, suggesting an interplay between these cellular processes, although their dynamic features are still unknown. A number of pathologies including metabolic, neurodegenerative and cardiovascular diseases, cancer, inflammation, and viral infections are associated with ER stress, leading to a growing interest in targeting components of the UPR as a therapeutic strategy. Melatonin has a variety of antioxidant, anti‐inflammatory, and antitumor effects. As such, it modulates apoptosis and autophagy in cancer cells, neurodegeneration and the development of liver diseases as well as other pathologies. Here, we review the effects of melatonin on the main ER stress mechanisms, focusing on its ability to regulate the autophagic and apoptotic processes. As the number of studies that have analyzed ER stress modulation by this indole remains limited, further research is necessary for a better understanding of the crosstalk between ER stress, autophagy, and apoptosis and to clearly delineate the mechanisms by which melatonin modulates these responses.     

巨噬细胞铁死亡与动脉粥样硬化

动脉粥样硬化是多种心血管疾病的病理基础,其导致的心血管疾病仍然是全球人类死亡的主要原因。铁死亡是一种铁离子依赖性非凋亡形式的细胞死亡方式,与多种生理机制密切相关。近些年来研究发现巨噬细胞铁死亡对于动脉粥样硬化的发生发展具有十分重要的作用。文章从巨噬细胞铁代谢水平失衡出发,就巨噬细胞铁死亡与脂质过氧化、炎症、氧化应激等方面的相互作用,综述了巨噬细胞铁死亡与动脉粥样硬化之间的关系,以期为动脉粥样硬化发病机制的研究提供新的思路。     

低剪切应力与动脉粥样硬化形成研究新进展

动脉粥样硬化病变为动脉内膜损伤诱导性增生,好发于动脉的分叉和分支等低剪切应力(LSS)区域。LSS通过激活细胞上的膜感受器和细胞内信号转导而调节基因表达以及表型的转变,在动脉粥样硬化病变的发生和发展中起着重要作用。本文综述了LSS与内皮细胞炎症、内皮间质转化、内皮细胞自噬间的关系及其调控机制,期望为动脉粥样硬化防治提供新的思路和策略。     

Traditional Chinese herbal extracts inducing autophagy as a novel approach in therapy of nonalcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD) is one of the leading causes of chronic liver diseases around the world due to the modern sedentary and food-abundant lifestyle, which is characterized by excessive fat accumulation in the liver related with causes other than alcohol abuse. It is widely acknowledged that insulin resistance, dysfunctional lipid metabolism, endoplasmic reticulum stress, oxidative stress, inflammation, and apoptosis/necrosis may all contribute to NAFLD. Autophagy is a protective self-digestion of intracellular organelles, including lipid droplets(lipophagy), in response to stress to maintain homeostasis. Lipophagy is another pathway for lipid degradation besides lipolysis. It is reported that impaired autophagy also contributes to NAFLD. Some studies have suggested that the histological characteristics of NAFLD(steatosis, lobular inflammation, and peri-sinusoid fibrosis) might be improved by treatment with traditional Chinese herbal extracts, while autophagy may be induced. This review will provide insights into the characteristics of autophagy in NAFLD and the related role/mechanisms of autophagy induced by traditional Chinese herbal extracts such as resveratrol, Lycium barbarum polysaccharides, dioscin, bergamot polyphenol fraction, capsaicin, and garlic-derived S-allylmercaptocysteine, which may inhibit the progression of NAFLD. Regulation of autophagy/lipophagy with traditional Chinese herbal extracts may be a novel approach for treating NAFLD, and the molecular mechanisms should be elucidated further in the near future.     

小凹及小凹蛋白1：胆固醇逆向转运与炎症应答的共同分子平台

脂质紊乱和炎症反应在动脉粥样硬化的发生发展中发挥了重要的作用。其中胆固醇的逆向转运能力是决定动脉粥样硬化进程与转归的关键。大量文献及研究结果显示,小凹以及小凹蛋白1既在荷脂细胞胆固醇流出中发挥转运中心和关键分子作用,也在炎症反应中发挥介导抗炎的信号转导作用。因此,小凹以及小凹蛋白1可能是荷脂细胞胆固醇逆向转运和炎症应答的共同分子平台。     

Lipid disorders and their relevance to outcomes in chronic kidney disease

Cardiovascular disease is the major cause of death in patients with chronic kidney disease (CKD). Cardiovascular disease and many other complications of CKD are mediated by oxidative stress, inflammation, and dyslipidemia. This review provides a concise overview of the nature and mechanisms of CKD-induced lipid disorders and their adverse consequences. Lipid abnormalities in end-stage renal disease are characterized by: (a) reduced serum apoA-1 and high-density lipoprotein (HDL) concentrations, impaired HDL maturation and defective HDL antioxidant, anti-inflammatory and reverse cholesterol transport properties; (b) impaired clearance of very low-density lipoprotein and chylomicrons by the muscle and adipose tissue and of their remnants by the liver leading to hypertriglyceridemia, accumulation of intermediate-density lipoprotein and chylomicron remnants, and (c) oxidative modification of LDL and lipoprotein remnants favored by their structural abnormalities, oxidative stress, and impaired HDL antioxidant activity. Together these abnormalities result in: (a) uptake of oxidized LDL and remnant particles by macrophages and resident cells in the artery wall which along with impaired HDL-mediated reverse cholesterol transport causes foam cell formation and atherosclerosis, (b) production of inflammatory mediators and reactive oxygen species by leukocytes and macrophages in response to stimulation by oxidized LDL and phospholipids leading to intensification of oxidative stress and inflammation, (c) dissemination of oxidative stress by circulating oxidized lipids and lipoproteins via lipid peroxidation chain reaction, (d) heightened injurious effects of oxidative stress and inflammation due to diminished antioxidant, anti-inflammatory and antithrombotic activities of HDL, and finally (e) impaired ability of very low-density lipoprotein and chylomicron to deliver lipid fuel to muscle and adipose tissue contributing to muscle weakness and cachexia which commonly occur in end-stage renal disease patients.     

High-density lipoprotein: Is it always atheroprotective?

High-density lipoproteins (HDLs) are appropriately recognized for their many atheroprotective functions, including reverse cholesterol transport, as well as antioxidant, anti-inflammatory, and antithrombotic effects. Furthermore, the inverse relationship between HDL cholesterol and atherosclerosis is well documented in many populations. However, there is an increasing body of evidence that there are circumstances in which HDL may not be protective, and may in fact paradoxically promote vascular inflammation and oxidation of low-density lipoproteins. Recent studies have provided insight as to specific chemical modifications and structural changes within HDL associated with this phenotype. The presence of proinflammatory HDL coincides with conditions associated with chronic systemic inflammation, including atherosclerosis.     

ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS

Ataxia-telangiectasia mutated (ATM) is a cellular damage sensor that coordinates the cell cycle with damage-response checkpoints and DNA repair to preserve genomic integrity. However, ATM also has been implicated in metabolic regulation, and ATM deficiency is associated with elevated reactive oxygen species (ROS). ROS has a central role in many physiological and pathophysiological processes including inflammation and chronic diseases such as atherosclerosis and cancer, underscoring the importance of cellular pathways involved in redox homeostasis. We have identified a cytoplasmic function for ATM that participates in the cellular damage response to ROS. We show that in response to elevated ROS, ATM activates the TSC2 tumor suppressor via the LKB1/AMPK metabolic pathway in the cytoplasm to repress mTORC1 and induce autophagy. Importantly, elevated ROS and dysregulation of mTORC1 in ATM-deficient cells is inhibited by rapamycin, which also rescues lymphomagenesis in Atm-deficient mice. Our results identify a cytoplasmic pathway for ROS-induced ATM activation of TSC2 to regulate mTORC1 signaling and autophagy, identifying an integration node for the cellular damage response with key pathways involved in metabolism, protein synthesis, and cell survival.