肠道菌群代谢产物与心肌纤维化关系的研究进展

心肌纤维化(MF)以细胞外基质积聚、成纤维细胞活化、转化为肌成纤维细胞为特征,是心脏损伤后心脏重构的特征之一,MF包括两种基本类型:反应性纤维化和修复性纤维化,在心室重构的过程中,两种纤维化常合并存在,MF可导致充血性心力衰竭、恶性心律失常和猝死,成为心室重构持续发展和难以逆转的重要原因.一些研究表明,肠道菌群代谢产物...     

炎症调控心肌损伤后的修复

近年来心血管疾病患病率和死亡率持续上升。心肌细胞损伤和凋亡使心肌细胞大量丧失,当心肌细胞数量减少到一定程度时,会被纤维瘢痕不可逆替代,愈合过程中出现心室重塑、心律失常、心功能障碍,最终导致心力衰竭。新近研究发现新生小鼠心肌受损后,会发生急性炎症反应,血液中的中性粒细胞、单核细胞和巨噬细胞迅速聚集到受损的心肌区域释放细胞因子以调节受损组织的微环境进而促进心肌再生和心脏修复。当对损伤心脏进行免疫抑制后,受损区域却不能再生,心脏修复受到抑制。而过度的炎症反应则会促进纤维化瘢痕的形成,严重影响心肌梗死后心肌细胞再生和心脏修复。及时将梗死心脏中的促炎症信号抑制,可以促进损伤组织的修复。炎症、组织纤维化以及血管新生不足是抑制心肌再生的三大主要障碍。炎症反应调控心肌细胞再生和修复,同时对心肌纤维化和血管形成也有影响。因此,本文就炎症反应在心肌损伤后修复和心肌再生中的作用的研究进展进行综述,旨在为相关科学问题的研究提供思路。     

终末期冠心病的干细胞移植治疗

自从1977年开展PTCA及10年后的支架植入术,心肌梗死患者的死亡率和远期预后明显改善。但是梗塞血管再通虽能挽救缺血顿抑心肌,但是无法促使已梗死的心肌细胞再生。随着心肌梗死区的纤维化和疤痕形成,梗死区室壁延展变薄,发生心室重构,成为部分心梗患者后期出现心功能不全和心源性死亡的主要原因犤1犦。因此如果在心肌梗死发生后采取治疗措施修复受损心肌,促进梗死心肌细胞再生,将会明显改善心肌梗死患者的预后。最近十余年,人们在动物实验中发现肌样细胞或多能干细胞移植可以修复梗死心肌,改善受损的心脏功能犤2～4犦,这一突破性的发现使…     

肌成纤维细胞在心肌梗死后重构中的作用及机制

成纤维细胞在心肌梗死后心脏修复和重构中起着重要作用,参与其中多个环节,调节细胞外基质的代谢,具有分化为肌成纤维细胞的潜能。肌成纤维细胞比成纤维细胞的表型更丰富,能更有效地对坏死细胞及间质进行修复和重构。然而,持久的肌成纤维细胞激活则会引起病理性纤维化,导致心律失常、心肌僵硬、心力衰竭的发生。     

CC10与小鼠心肌梗死后心肌纤维化的关系

目的 探究克拉拉细胞10-kDa蛋白(CC10)与心肌梗死后心肌纤维化的关系。方法 取6～8周龄SPF级雄性C57BL/6小鼠32只,随机分为模型组与假手术组,每组16只。模型组小鼠结扎冠状动脉左前降支,构建心肌梗死模型。检测小鼠心脏的CC10 mRNA、α-SMA mRNA表达及肺内的CC10 mRNA表达。观察小鼠心肌纤维化程度;分析CC10在组织层面和蛋白表达的变化;明确CC10在心脏梗死区定位的细胞类型;测定CC10 mRNA随心脏成纤维细胞增殖的表达变化。结果 心肌梗死后,随着心肌纤维化加重,CC10在心脏与肺组织中的表达上升(P<0.05)。CC10的表达主要定位于心脏梗死区的成纤维细胞,且伴随成纤维细胞增殖,CC10的表达不断增加。结论 伴随心肌纤维化程度加重,CC10在小鼠心肌梗死后的心脏与肺组织中表达上升。     

心肌成纤维细胞的特性和调节

心肌成纤维细胞在心脏中是数量最大的细胞,它们通过维持细胞外基质平衡在受损或衰竭心脏中纤维化心肌重塑发挥重要作用。它既调节正常的心脏功能,也参与高血压病、心肌梗死和心力衰竭等的不良心肌重塑。综述心肌成纤维细胞的特性,包括起源、机械电特性、细胞外基质代谢中的作用,以及正常和病理状态下心肌成纤维细胞对环境刺激的功能反应和分泌生物活性因子的能力,并总结以心肌成纤维细胞为靶细胞调节心肌纤维化的研究现状。     

心肌球和心肌球源性干细胞的研究进展

1心肌球和心肌球源性干细胞来源于心脏,具有无性繁殖、自我更新、多向分化的潜能,移植到受损心脏后能通过直接再生、旁分泌及激活内源性修复等多种修复机制,降低心肌梗死面积、抑制心室重塑、提高心脏功能等。联合应用基因修饰、组织工程等为进一步优化心肌梗死的治疗效果带来了新的希望。     

炎症在心肌损伤和修复中的作用

心肌损伤会引起强烈的炎症反应,炎性细胞浸润到局部组织,激活肌成纤维细胞和血管内皮细胞,促进组织修复和瘢痕形成,同时引起心肌组织不良的纤维化重塑,加剧心肌细胞凋亡,导致心律失常。一系列证据显示,心肌梗死后免疫炎症反应在心室重构中发挥关键性作用。文文主要探讨免疫炎症反应相关效应细胞和分子信号参与心肌损伤和修复,并强调采用成熟有效的免疫调节治疗策略有助于预防不良心室重构,减少心力衰竭的发生。     

微小RNA-21-5p促进梗死心肌纤维化加重心力衰竭的作用及机制

目的探讨微小RNA-21-5p(miR-21-5p)在心肌梗死后心力衰竭中的作用及相关机制。方法构建小鼠心肌梗死模型,利用实时荧光定量PCR方法分析梗死心肌中miR-21-5p的表达变化;构建miR-21-5p过表达慢病毒,通过在体感染合并心肌梗死小鼠模型,采用超声心动图及免疫组化方法明确miR-21-5p对心肌梗死后心肌纤维化、心力衰竭的影响;体外进行miR-21-5p慢病毒感染,采用细胞划痕试验及细胞计数检测明确miR-21-5p对心脏成纤维细胞功能的影响。结果小鼠梗死心肌中miR-21-5p的表达是假手术组小鼠的1.75倍(t=8.633,P<0.01);与阴性对照组相比,miR-21-5p可导致心肌梗死后心功能进一步恶化(左室射血分数:31.62%±7.63%比42.69%±4.47%,t=2.800,P=0.02),并加重梗死心肌纤维化程度(42.61%±6.73%比23.23%±4.07%,t=3.470,P=0.01);miR-21-5p可下调Smad7表达(0.72倍,t=3.432,P=0.01),促进心脏成纤维细胞的增殖(1.42倍,t=5.855,P<0.01)和迁移能力(1.41倍,t=6.658,P<0.01)。结论 miR-21-5p通过下调Smad7表达,增强心脏成纤维细胞的增殖和迁移能力,加重心肌梗死后心肌纤维化和心力衰竭。     

心脏肌成纤维细胞活化的力学调控

在心肌修复或纤维化过程中,以成纤维细胞为主的多种前体细胞向心脏肌成纤维细胞(CMFs)活化,合成大量细胞外基质成分,并持续存在于心肌瘢痕中。CMFs活化除了受促纤维化因子的调控外,还受力学因素的影响。ECM刚度增加及循环应变的改变能促进CMFs活化推动心肌纤维化持续进展。通过调控CMFs对机械应力的敏感性来抑制CMFs活化的方法有可能成为心肌纤维化治疗的新选择。     

Origin of Developmental Precursors Dictates the Pathophysiologic Role of Cardiac Fibroblasts

Fibroblasts in the heart play a critical function in the secretion and modulation of extracellular matrix critical for optimal cellular architecture and mechanical stability required for its mechanical function. Fibroblasts are also intimately involved in both adaptive and nonadaptive responses to cardiac injury. Fibroblasts provide the elaboration of extracellular matrix and, as myofibroblasts, are responsible for cross-linking this matrix to form a mechanically stable scar after myocardial infarction. By contrast, during heart failure, fibroblasts secrete extracellular matrix, which manifests itself as excessive interstitial fibrosis that may mechanically limit cardiac function and distort cardiac architecture (adverse remodeling). This review examines the hypothesis that fibroblasts mediating scar formation and fibroblasts mediating interstitial fibrosis arise from different cellular precursors and in response to different autocoidal signaling cascades. We demonstrate that fibroblasts which generate scars arise from endogenous mesenchymal stem cells, whereas those mediating adverse remodeling are of myeloid origin and represent immunoinflammatory dysregulation.     

Akt-dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction

Myocardial infarction is a leading cause of death, and cardiac rupture following myocardial infarction leads to extremely poor prognostic feature. A large body of evidence suggests that Akt is involved in several cardiac diseases. We previously reported that Akt-mediated Girdin phosphorylation is essential for angiogenesis and neointima formation. The role of Girdin expression and phosphorylation in myocardial infarction, however, is not understood. Therefore, we employed Girdin-deficient mice and Girdin S1416A knock-in (Girdin^SA/SA) mice, replacing the Akt phosphorylation site with alanine, to address this question. We found that Girdin was expressed and phosphorylated in cardiac fibroblasts in vitro and that its phosphorylation was crucial for the proliferation and migration of cardiac fibroblasts. In vivo, Girdin was localized in non-cardiomyocyte interstitial cells and phosphorylated in α-smooth muscle actin-positive cells, which are likely to be cardiac myofibroblasts. In an acute myocardial infarction model, Girdin^SA/SA suppressed the accumulation and proliferation of cardiac myofibroblasts in the infarcted area. Furthermore, lower collagen deposition in Girdin^SA/SA mice impaired cardiac repair and resulted in increased mortality attributed to cardiac rupture. These findings suggest an important role of Girdin phosphorylation at serine 1416 in cardiac repair after acute myocardial infarction and provide insights into the complex mechanism of cardiac rupture through the Akt/Girdin-mediated regulation of cardiac myofibroblasts.     

Cardiac stem cell therapy for myocardial regeneration. A clinical perspective

Myocardial infarction and other pathologic conditions of the heart result in loss of cardiomyocytes, scar formation, ventricular remodeling, and eventually heart failure. Since pharmacologic and interventional strategies fail to regenerate dead myocardium, heart failure continues to be a major health problem worldwide. Recent studies in animal models of myocardial infarction and heart failure have demonstrated that various subsets of adult primitive cells can regenerate functional cardiomyocytes and cardiac vasculature with improvement in cardiac structure and function. Small clinical trials of cell therapy in patients with myocardial infarction and ischemic cardiomyopathy have recapitulated these beneficial effects in humans with infarct size reduction and improvement in ejection fraction, myocardial perfusion, and wall motion. Several phenotypically distinct cell populations have been utilized for cardiac regeneration, and the relative merits of one cell over another remain to be determined. The recent discovery of adult cardiac stem cells has sparked intense hope for myocardial regeneration with cells that are from the heart itself and are thereby inherently programmed to reconstitute cardiac tissue. The purpose of this review is to summarize the evidence regarding the feasibility of cardiac repair in humans via adult stem/progenitor cells, and to discuss the potential utility of cardiac stem cells for therapeutic myocardial regeneration.     

Myocardial repair with autologous skeletal myoblasts: a review of the clinical studies and problems

Stem cell therapy for myocardial repair after myocardial infarction is a new and promising treatment modality. Currently, bone marrow derived stem cells are used in clinical studies to evaluate its beneficial effect on repair of infarcted/hibernating myocardium in the subacute phase after myocardial infarction. Whereas skeletal myoblasts are nowadays under investigation in the setting of scar repair in chronic congestive heart failure patients. The mechanism of bone marrow derived stem cells is probably mainly related to induction and stimulation of angiogenesis, whereas skeletal myoblasts are more likely to contribute to recovery of left ventricular function by the direct engraftment of contractile cells and hypothetically indirect by stimulation of native and circulation stem cells to home into the scarred tissue. This review will focus on the use of skeletal myoblasts in all clinical studies presented sofar and will discuss several issues like: different transplantation methods, potential mechanism of effect, potential risks like arrhythmia and future concepts. As the target population of skeletal myoblast transplantation is chronic post myocardial infarction heart failure patients, ventricular arrhythmias are very likely to occur. This review will specially address the presence of ventricular arrhythmias observed in some clinical studies and the pre-clinical data on the electrophysiology of skeletal myotubes and its relationship to the surrounding myocardium.     

Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling

The cardiac extracellular matrix is a dynamic structural support network that is both influenced by, and a regulator of, pathological remodeling and hypertrophic growth. In response to pathologic insults, the adult heart reexpresses the secreted extracellular matrix protein periostin (Pn). Here we show that Pn is critically involved in regulating the cardiac hypertrophic response, interstitial fibrosis, and ventricular remodeling following long-term pressure overload stimulation and myocardial infarction. Mice lacking the gene encoding Pn (Postn) were more prone to ventricular rupture in the first 10 days after a myocardial infarction, but surviving mice showed less fibrosis and better ventricular performance. Pn(-/-) mice also showed less fibrosis and hypertrophy following long-term pressure overload, suggesting an intimate relationship between Pn and the regulation of cardiac remodeling. In contrast, inducible overexpression of Pn in the heart protected mice from rupture following myocardial infarction and induced spontaneous hypertrophy with aging. With respect to a mechanism underlying these alterations, Pn(-/-) hearts showed an altered molecular program in fibroblast function. Indeed, fibroblasts isolated from Pn(-/-) hearts were less effective in adherence to cardiac myocytes and were characterized by a dramatic alteration in global gene expression (7% of all genes). These are the first genetic data detailing the function of Pn in the adult heart as a regulator of cardiac remodeling and hypertrophy.     

直接心脏重编程的研究进展

直接心脏重编程是指将成纤维细胞转变为功能性心肌细胞的技术,转录因子最先应用到直接重编程中,此后的研究表明,microRNAs和一些小分子等对优化这一技术表现出极大的潜能。近年来,直接心脏重编程技术不断发展,在心肌梗死、心力衰竭等疾病研究中取得突破。现将近年来对直接心脏重编程的研究进行综述,展望直接重编程对心脏疾病的治疗前景,探索心血管疾病治疗的一个新思路。     

生物材料在心脏再生修复过程中的应用

心肌梗死是冠状动脉急性、持续性缺血缺氧所引起的心肌坏死,发病率和死亡率居高不下。虽然通过冠状动脉介入或溶栓药物等治疗手段恢复血供,能提高患者的生存率,但难以挽救梗死区丢失的心肌细胞,而成年哺乳动物心脏自身修复能力有限是造成心肌纤维化,最终进展为心力衰竭的主要因素。长期以来,已有的治疗手段难以逆转心肌梗死后的心力衰竭进程。细胞移植有望成为促进梗死修复与再生最有前景的治疗方法,由于缺血缺氧微环境导致移植后有限的干细胞存活和保留,结果不是很理想。而脱细胞生物材料以促进血管生成和减轻纤维化显示了临床前治疗潜力。该综述概述了各种脱细胞生物材料及通过微创的方式进行心外膜修复及心肌内注射促进心脏再生、改善心脏功能的利与弊,为将来利用脱细胞生物材料结合优化的药物促进心肌再生提供参考。     

miR-148b参与心肌梗死后心脏纤维化的作用及机制

目的 探讨miR-148b参与大鼠心肌梗死后心脏纤维化的作用及可能机制。方法 采用结扎大鼠冠状动脉左前降支方法制作大鼠心肌梗死模型,RT-PCR法评价大鼠心脏miR-148b表达水平;应用生物信息学方法预测miR-148b靶基因;采用Western blot方法评价大鼠心脏同源性磷酸酶-张力蛋白（phosphatase and tensin homologue,PTEN）及α-平滑肌蛋白（α-smooth muscle actin,α-SMA）蛋白表达水平;四甲基偶氮唑盐比色（MTT）法检测心脏成纤维细胞增殖能力;应用天狼猩红染色评价心脏纤维化病理改变。结果 大鼠心肌梗死组,梗死周边区纤维化程度显著增加,miR-148b表达显著上调（P<0.01）;miR-148b与预测靶基因PTEN mRNA有结合位点;大鼠心肌梗死组,梗死周边区PTEN表达显著下调（P<0.01）;在心脏成纤维细胞中过表达miR-148b,PTEN的蛋白表达水平显著下调（P<0.01）,α-SMA蛋白表达水平显著上调（P<0.01）,细胞增殖能力显著增强（P<0.05）;在AngII诱导心肌纤维化细胞模型中,抑制miR-148b,PTEN蛋白表达水平显著上调（P<0.05）,α-SMA蛋白表达水平显著下调（P<0.01）,心脏成纤维细胞增殖显著减少（P<0.01）。结论 miR-148b通过PTEN参与心肌梗死后心脏纤维化作用。     

Autoimmunity in myocardial infarction

Myocardial infarction is associated with an immune response. Physiological inflammation response causes self-repair and protection, while pathological autoimmune response leads to ventricular remodeling and heart failure. Laying emphasis on regulating the immune function may become a new target for the prevention of heart failure after myocardial infarction. This review focuses on the mechanism of immune-mediated ventricular remodeling and the immune therapy after myocardial infarction.     

Human embryonic stem cells for cardiovascular repair

The critical loss of functional cardiomyocytes causes severe deterioration of pump function, resulting in heart failure. The possibility to regenerate or repair damaged or ischemic cardiac tissue is a great challenge for the future treatment of end-stage heart failure. As cardiomyocytes cannot be regenerated in adults, current therapeutic modalities for the treatment of end-stage heart failure are limited and include medical therapy, mechanical left ventricular assist devices, and cardiac transplantation. This review will focus on the potential use of human embryonic stem (hES) cell-derived cardiomyocytes and vascular cells, as a therapeutic tool for the treatment of myocardial infarction and end-stage heart failure.