肝源性肝细胞生长因子的研究与临床应用现状

肝源性肝细胞生长因子的研究与临床应用现状北京军区总医院（１００７００）林梅肝细胞在受到损伤后具有很强的再生功能，这种再生的调控受内分泌、旁分泌和自分泌等多种因素的影响。目前已发现有不少影响肝细胞再生的因子和激素，除了一些非特异性的作用相对较为广泛的调...     

血小板的止血外作用

血小板主要参与止血、加速凝血和伤口愈合等过程。随着研究的深入，人们发现血小板还有以下重要特性：（1）分泌多种血管生成促进因子，并可直接参与血管的形成；（2）分泌多种炎症因子，参与炎症反应；（3）诱导和促进动脉粥样硬化；（4）调控P2Y12表达；（5）调节血脂；（6）参与天然免疫。     

慢性心力衰竭与血浆一氧化氮、内皮素及前列环素动态变化的关系

近年研究证明，循环内分泌和心脏血管组织的自分泌、旁分泌激活参与了心力衰竭的病理生理过程。其中一氧化氮（NO）、内皮素（ET）和前列环素（PGI2）在心力衰竭的发生发展中起着重要作用。本文旨在研究慢性心力衰竭（CHF）患者血浆NO、ET和PGI2含量的变化，进一步揭示其在CHF病理生理过程中的意义。     

内皮细胞代谢调控在血管性疾病中的研究进展

内皮细胞（endothelial cell,EC）代谢在机体正常发育和疾病发生中发挥着重要作用。与其他类型细胞相比,EC高度依赖糖酵解、脂肪酸氧化和氨基酸代谢等,以使其具备将血液中氧气和营养物质运输至周围组织以及在乏氧无血管区域进行血管生成的能力。随着研究深入,越来越多代谢途径被发现参与调控EC增殖、迁移和血管生成等过程。异常的内皮细胞代谢导致EC增殖、迁移以及血管生成等能力丧失或增强, 进而引发动脉粥样硬化、心肌梗死、肢体缺血等血管性疾病发生,靶向EC代谢方式是血管性疾病的潜在治疗靶点。本文就EC代谢调控在血管性疾病中作用的研究进展进行阐述,以期为血管性疾病的防治提供新思路。     

甾醇调节元件结合蛋白在子宫内膜癌发生发展中的作用机制研究进展

甾醇调节元件结合蛋白（Sterol regulatory element-binding protein-1, SREBP-1）是调控脂肪酸从头合成的关键转录因子。子宫内膜癌（Endometrial carcinoma,EC）组织中SREBP-1表达上调。磷脂酰肌醇3-羟基激酶（phosphatidylinositol 3-hydroxy kinase, PI3K）/蛋白激酶B(protein kinase B, PKB/Akt)致癌信号通路、抑癌基因P53可通过促进SREBP-1高表达,参与EC的发生发展。SREBP-1可作为脂肪酸从头合成的关键调节因子,调控脂肪酸从头合成,并调控ATP柠檬酸裂解酶、乙酰辅酶A羧化酶、脂肪酸合成酶等脂肪酸从头合成过程中关键酶基因表达,参与异常脂肪形成途径,促进EC的发生发展。     

心外膜与心脏修复再生

在所有脊椎动物中,心外膜是包裹心脏的一层间皮组织。在心脏发育和修复再生过程中,这个结构是重要细胞如血管平滑肌细胞、周细胞和成纤维细胞等的来源,并且分泌对心肌细胞的增殖和存活至关重要的因子。当心脏受损时心外膜会被重新激活,并刺激上皮向间充质转变中的发育基因程序。现就近年来对心外膜与心脏修复和再生的相关机制研究进行总结,旨在利用心外膜的再生潜力进行心脏修复并提出未来的观点,以突出新兴的治疗策略。     

生长激素对心脏功能的影响

心脏、血管是生长激素（GH）、胰岛素样生长因子（IGF）-1的靶器官之一，心脏可通过自分泌、旁分泌形式产生GH、IGF-1，而后者可通过改变Ca^2 浓度等调节心肌细胞的功能。GH增多主要使心脏向心性肥大、心输出量下降；而GH缺乏可引起心肌变薄、泵功能下降。相应采取GH抑制或替代治疗可不同程度地改善心脏功能，控制病情发展。     

金属蛋白酶组织抑制因子1抗关节炎大鼠滑膜炎症及血管新生的研究

类风湿关节炎（rheumatoid arthritis，RA）是一种慢性的以关节症状为主的全身性的自身免疫性疾病．目前的研究表明炎症滑膜所分泌的许多细胞因子促进关节滑膜新生血管形成是RA病理过程的中心环节。新生血管形成（angiogenesis）是一个涉及内皮细胞、细胞外基质、可溶性细胞因子的复杂的、多步骤的、协调的连续过程．受多种因素调控．主要取决于血管生成促进因子和血管生成抑制因子之间的平衡。金属蛋白酶组织抑制因子1（tissue inhibitor of metalloproteinase 1 ，TIMP1）是近年来发现的MMPs的天然抑制剂。是相对分子质量为285000的糖蛋白。TIMPs在多个环节抑制MMPs的活性．亦可抑制新生血管形成．如阻碍MMPs介导的内皮细胞移动。抑制基质中促血管生成因子的释放，     

肾素-血管紧张素系统与胰腺炎

循环肾素一血管紧张素系统（RAS）是复杂的神经内分泌系统，也是应激反应系统，在维持机体血压和水、电解质平衡中发挥重要作用。血管紧张素原由肝脏产生，在肾脏产生的肾素作用下转换为血管紧张素Ⅰ（AngⅠ），由肺脏产生的血管紧张素转换酶（ACE）转换为血管紧张素Ⅱ（AngⅡ），在其他一些酶的作用下还可以产生其他一些活性物质，如AngⅡ、AngⅣ（Ang3～8）和Ang1～7，AngⅡ是主要的活性物质。血管紧张素受体包括AT1、AT2、AT3、AT4四种，AT1又分两个亚型，AT1a和AT1b。已知大部分AngⅡ活性是由AT1受体介导的。最近研究证明，很多组织器官存在局部RAS，如大脑、心脏、肾脏、性腺、肾上腺、胰腺等，这种组织RAS独立地通过旁分泌和（或）自分泌方式在各自组织器官的生理和病理生理过程中发挥重要作用，应用局部组织RAS拮抗剂可对这些组织器官疾病产生积极作用。[第一段]     

血管内皮生长因子对培养内皮细胞合成一氧化氮的影响

目的 :探讨血管内皮生长因子 （VEGF） /血管渗透因子 （VPF）对内皮细胞 （EC）分泌一氧化氮 （NO）的影响。方法 :将培养的人脐静脉内皮细胞 （HUVEC）随机分为 6组 （n=6 /组 ） :1正常对照组 ;2 VEGF 1ng/ m l;3VEGF 10ng/ m l;4VEGF 10 0 ng/ m l;5低氧组 ;6低氧组 +VEGF 10 0 ng/ m l。采用硝酸还原酶法测定培养液中的 NO2 - ,NO3 -的含量以反映 NO水平。结果 :VEGF促进正常 EC分泌 NO,在一定浓度范围内呈剂量依赖性 ;低氧损伤 EC,使其分泌 NO减少 ;VEGF 10 0 ng/ ml预处理可保护 EC免受低氧损害 ,保持正常分泌 NO的功能。结论 :VEGF能够调节 EC的功能 ,为其促血管形成作用中 EC分裂、增殖、迁移奠定物质基础     

Angiogenesis in liver regeneration and fibrosis: “a double-edged sword”

Angiogenesis, defined as the formation of new microvasculature from preexisting blood vessels and mature endothelial cells, plays a major role in wound healing and scar formation, and it is associated with inflammatory responses. Angiogenesis can occur in physiological conditions, such as during liver regeneration, and in pathological situations, such as during the progression of fibrosis to cirrhosis and also during tumor angiogenesis. Cellular cross-talk among liver sinusoidal endothelial cells (LSECs), hepatic stellate cells and hepatocytes is believed to play an important role in the angiogenesis process during both liver regeneration and development of cirrhosis. In addition to mature endothelial cells, bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) have been recently identified for their contribution to post-natal vasculogenesis/angiogenesis. In vivo, EPCs are mobilized into the peripheral blood in response to tissue ischemia or traumatic injury, migrate to the sites of injured endothelium and differentiate into mature endothelial cells. In our recent studies, we have explored the role of EPC-mediated angiogenesis in liver regeneration and/or cirrhosis. Results have demonstrated significantly increased endogenous levels of circulating EPCs in cirrhotic patients in comparison to the controls. Also, EPCs from cirrhotic patients have been observed to stimulate substantial angiogenesis by resident LSECs in vitro via paracrine factors such as vascular endothelial growth factor and platelet-derived growth factor. This review gives an overview of the angiogenesis process in liver regeneration and disease and discusses a new mechanism for intrahepatic angiogenesis mediated by BM-derived EPCs.     

Neuronal sirtuin1 mediates retinal vascular regeneration in oxygen-induced ischemic retinopathy

Regeneration of blood vessels in ischemic neuronal tissue is critical to reduce tissue damage in diseases. In proliferative retinopathy, initial vessel loss leads to retinal ischemia, which can induce either regrowth of vessels to restore normal metabolism and minimize damage, or progress to hypoxia-induced sight-threatening pathologic vaso-proliferation. It is not well understood how retinal neurons mediate regeneration of vascular growth in response to ischemic insults. In this study we aim to investigate the potential role of Sirtuin 1 (Sirt1), a metabolically-regulated protein deacetylase, in mediating the response of ischemic neurons to regulate vascular regrowth in a mouse model of oxygen-induced ischemic retinopathy (OIR). We found that Sirt1 is highly induced in the avascular ischemic retina in OIR. Conditional depletion of neuronal Sirt1 leads to significantly decreased retinal vascular regeneration into the avascular zone and increased hypoxia-induced pathologic vascular growth. This effect is likely independent of PGC-1α, a known Sirt1 target, as absence of PGC-1α in knockout mice does not impact vascular growth in retinopathy. We found that neuronal Sirt1 controls vascular regrowth in part through modulating deacetylation and stability of hypoxia-induced factor 1α and 2α, and thereby modulating expression of angiogenic factors. These results indicate that ischemic neurons induce Sirt1 to promote revascularization into ischemic neuronal areas, suggesting a novel role of neuronal Sirt1 in mediating vascular regeneration in ischemic conditions, with potential implications beyond retinopathy.     

Stem cell mechanisms during left ventricular remodeling post-myocardial infarction:Repair and regeneration

Post-myocardial infarction(MI),the left ventricle(LV)undergoes a series of events collectively referred to as remodeling.As a result,damaged myocardium is replaced with fibrotic tissue consequently leading to contractile dysfunction and ultimately heart failure.LV remodeling post-MI includes inflammatory,fibrotic,and neovascularization responses that involve regulated cell recruitment and function.Stem cells(SCs)have been transplanted post-MI for treatment of LV remodeling and shown to improve LV function by reduction in scar tissue formation in humans and animal models of MI.The promising results obtained from the application of SCs post-MI have sparked a massive effort to identify the optimal SC for regeneration of cardiomyocytes and the paradigm for clinical applications.Although SC transplantations are generally associated with new tissue formation,SCs also secrete cytokines,chemokines and growth factors that robustly regulate cell behavior in a paracrine fashion during the remodeling process.In this review,the different types of SCs used for cardiomyogenesis,markers of differentiation,paracrine factor secretion,and strategies for cell recruitment and delivery are addressed.     

The angiogenic factor CCN1 promotes adhesion and migration of circulating CD34+ progenitor cells: potential role in angiogenesis and endothelial regeneration

Tissue regeneration involves the formation of new blood vessels regulated by angiogenic factors. We reported recently that the expression of the angiogenic factor CCN1 is up-regulated under various pathophysiologic conditions within the cardiovascular system. Because CD34+ progenitor cells participate in cardiovascular tissue regeneration, we investigated whether CCN1-detected for the first time in human plasma-promotes the recruitment of CD34+ progenitor cells to endothelial cells, thereby enhancing endothelial proliferation and neovascularization. In this study, we demonstrated that CCN1 and supernatants from CCN1-stimulated human CD34+ progenitor cells promoted proliferation of endothelial cells and angiogenesis in vitro and in vivo. In addition, CCN1 induced migration and transendothelial migration of CD34+ cells and the release of multiple growth factors, chemokines, and matrix metalloproteinase-9 (MMP-9) from these cells. Moreover, the CCN1-specific integrins alpha(M)beta(2) and alpha(V)beta(3) are expressed on CD34+ cells and CCN1 stimulated integrin-dependent signaling. Furthermore, integrin antagonists (RGD-peptides) suppressed both binding of CCN1 to CD34+ cells and CCN1-induced adhesion of CD34+ cells to endothelial cells. These data suggest that CCN1 promotes integrin-dependent recruitment of CD34+ progenitor cells to endothelial cells, which may contribute to paracrine effects on angiogenesis and tissue regeneration.     

Bone marrow cells differentiate in cardiac cell lineages after infarction independently of cell fusion

Recent studies in mice have challenged the ability of bone marrow cells (BMCs) to differentiate into myocytes and coronary vessels. The claim has also been made that BMCs acquire a cell phenotype different from the blood lineages only by fusing with resident cells. Technical problems exist in the induction of myocardial infarction and the successful injection of BMCs in the mouse heart. Similarly, the accurate analysis of the cell populations implicated in the regeneration of the dead tissue is complex and these factors together may account for the negative findings. In this study, we have implemented a simple protocol that can easily be reproduced and have reevaluated whether injection of BMCs restores the infarcted myocardium in mice and whether cell fusion is involved in tissue reconstitution. For this purpose, c-kit-positive BMCs were obtained from male transgenic mice expressing enhanced green fluorescence protein (EGFP). EGFP and the Y-chromosome were used as markers of the progeny of the transplanted cells in the recipient heart. By this approach, we have demonstrated that BMCs, when properly administrated in the infarcted heart, efficiently differentiate into myocytes and coronary vessels with no detectable differentiation into hemopoietic lineages. However, BMCs have no apparent paracrine effect on the growth behavior of the surviving myocardium. Within the infarct, in 10 days, nearly 4.5 million biochemically and morphologically differentiated myocytes together with coronary arterioles and capillary structures were generated independently of cell fusion. In conclusion, BMCs adopt the cardiac cell lineages and have an important therapeutic impact on ischemic heart failure.     

缺氧对糖尿病血管内皮祖细胞的影响

血管内皮的损害和再生对维持血管的完整性十分重要,血循环中骨髓来源的血管内皮祖细胞有助于血管内皮的修复.局部缺血后,血管内皮祖细胞从骨髓动员到血液中,然后归巢到缺血组织处,在缺血处通过旁分泌生长因子或者渗入血管来促进新生血管形成.糖尿病患者的血管内皮祖细胞在缺氧条件下,功能受到损害,包括动员、附着、迁移、增殖等一系列环节...     

HMGB1-stimulated human primary cardiac fibroblasts exert a paracrine action on human and murine cardiac stem cells

High Mobility Box 1 Protein (HMGB1) is a cytokine released into the extracellular space by necrotic cells and activated macrophages in response to injury. We recently demonstrated that HMGB1 administration into the mouse heart during acute myocardial infarction induces cardiac tissue regeneration by activating resident cardiac c-kit⁺ cells (CSCs) and significantly enhances left ventricular function. In the present study it was analyzed the hypothesis that human cardiac fibroblasts (cFbs) exposed to HMGB1 may exert a paracrine effect on mouse and human CSCs. Human cFbs expressed the HMGB1 receptor RAGE. Luminex technology and ELISA assays revealed that HMGB1 significantly enhanced VEGF, PlGF, Mip-1α, IFN-γ, GM-CSF, Il-10, Il-1β, Il-4, Il-1ra, Il-9 and TNF-α in cFbs cell culture medium. HMGB1-stimulated cFbs conditioned media induced CSC migration and proliferation. These effects were significantly higher to those obtained when HMGB1 was added directly to the culture medium. In conclusion, we provide evidence that HMGB1 may act in a paracrine manner stimulating growth factor, cytokine and chemokine release by cFbs which, in turn, modulate CSC function. Via this mechanism HMGB1 may contribute to cardiac tissue regeneration.     

VEGF-A(164/165) and PlGF: roles in angiogenesis and arteriogenesis

Angiogenic cytokines such as vascular endothelial growth factor-A(164/165) (VEGF-A(164/165)) and placenta growth factor (PlGF) are being considered for therapeutic relief of coronary heart disease and other forms of tissue ischemia caused by atherosclerosis. Before proceeding further with clinical testing, it is important to determine what types of new blood vessels these cytokines actually induce and whether they could provide a useful new blood supply to ischemic tissues. In mice, VEGF-A(164/165) induced a transient angiogenic response (mother vessels, glomeruloid bodies, daughter capillaries), and stable arteriovenous malformations, arteriogenesis, and lymphangiogenesis; whereas PlGF only induced the formation of large, stable blood vessels. The large, long-lasting blood vessels induced by VEGF-A(164/165) and PlGF could provide an improved blood supply if positioned proximal to ischemic tissue, but VEGF-A(164/165)'s angiogenic response--which is short lived and accompanied by vascular hyperpermeability, edema, and fibrosis--would seem to offer little therapeutic benefit.     

Ectopic fat storage in heart, blood vessels and kidneys in the pathogenesis of cardiovascular diseases

In humans and most animal models, the development of obesity leads not only to increased fat depots in classical adipose tissue locations but also to significant lipid deposits within and around other tissues and organs, a phenomenon known as ectopic fat storage. The purpose of this review is to explore the possible locations of ectopic fat in key target-organs of cardiovascular control (heart, blood vessels and kidneys) and to propose how ectopic fat storage can play a role in the pathogenesis of cardiovascular diseases associated with obesity. In animals fed a high-fat diet, cardiac fat depots within and around the heart impair both systolic and diastolic functions, and may in the long-term promote heart failure. Accumulation of fat around blood vessels (perivascular fat) may affect vascular function in a paracrine manner, as perivascular fat cells secrete vascular relaxing factors, proatherogenic cytokines and smooth muscle cell growth factors. Furthermore, high amounts of perivascular fat could mechanically contribute to the increased vascular stiffness seen in obesity. Finally, accumulation of fat in the renal sinus may limit the outflow of blood and lymph from the kidney, which would alter intrarenal physical forces and promote sodium reabsorption and arterial hypertension. Taken together, ectopic fat storage in key target-organs of cardiovascular control may impair their functions, contributing to the increased prevalence of cardiovascular diseases in obese subjects.